Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics

ABSTRACT

Modified release formulations of gamma-hydroxybutyrate having improved dissolution and pharmacokinetic properties are provided, and therapeutic uses thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.18/075,980, filed Dec. 6, 2022, which is a continuation of U.S.application Ser. No. 17/497,393, filed Oct. 8, 2021, which is acontinuation-in-part of U.S. application Ser. No. 17/178,117, filed Feb.17, 2021, which is a continuation-in-part of U.S. application Ser. No.16/527,633, filed Jul. 31, 2019, now U.S. Pat. No. 11,065,224, which isa continuation of U.S. application Ser. No. 16/281,235, filed Feb. 21,2019, now U.S. Pat. No. 10,736,866, which is a continuation of U.S.application Ser. No. 15/655,924, filed Jul. 21, 2017, now U.S. Pat. No.10,272,062, which claims priority to U.S. Provisional Application No.62/365,812, filed Jul. 22, 2016, U.S. Provisional Application No.62/399,413, filed Sep. 25, 2016, and U.S. Provisional Application No.62/474,330, filed Mar. 21, 2017.

FIELD OF THE INVENTION

The present invention relates to modified release formulations ofgamma-hydroxybutyrate having improved pharmacokinetic (PK) properties,and to therapeutic uses thereof.

BACKGROUND

Narcolepsy is a devastating disabling condition. The cardinal symptomsare excessive daytime sleepiness (EDS), cataplexy (a sudden loss ofmuscle tone triggered by strong emotions, seen in approximately 60% ofpatients), hypnogogic hallucination (HH), sleep paralysis (SP), anddisturbed nocturnal sleep (DNS). Other than EDS, DNS is the most commonsymptom seen among narcolepsy patients.

The diagnosis of narcolepsy rests in part on clinical grounds. Whennarcolepsy is suspected, it is standard practice to administer anovernight polysomnogram (PSG) followed by a multiple sleep latency test(MSLT) to document the rapid eye movement (REM) abnormality thatcharacterizes the disorder. On the MSLT a mean sleep latency less thanor equal to 8 minutes and two or more sleep onset REM periods (SOREMPs)are required to confirm a diagnosis of Type 1 or Type 2 narcolepsy. Itis also possible, but infrequently preferred, that narcolepsy bediagnosed by measuring hypocretin in the cerebrospinal fluid (CSF) incases where the PSG and/or MSLT is not completed. For these cases, ahypocretin concentration of less than 110 pg/nL confirms a narcolepsyType 1 diagnosis.

One of the major treatments for narcolepsy is sodium oxybate, aneuroactive agent with a variety of Central Nervous System (CNS)pharmacological properties. The species is present endogenously in manytissues, where it acts as a neurotransmitter on a gamma-hydroxybutyrate(GHB) receptor (GHBR), and possesses neuromodulatory properties withsignificant effects on dopamine and Gamma-Aminobutyric Acid (GABA).Studies have suggested that sodium oxybate improves Rapid Eye MovementSleep (REM sleep, REMS) of narcoleptics in contrast to antidepressantdrugs.

Sodium oxybate is also known as sodium 4-hydroxybutanoate, orgamma-hydroxybutyric acid sodium salt, and has the following chemicalstructure:

Sodium oxybate is marketed commercially in the United States as Xyrem©.The product is formulated as an immediate release liquid solution thatis taken once immediately before bed, and a second time approximately2.5 to 4 hours later, in equal doses. Sleep-onset can be dramatic andfast, and patients are advised to be sitting in bed when consuming thedose. The most commonly reported side effects are confusion, depressivesyndrome, incontinence and sleepwalking.

When initiating treatment with sodium oxybate, careful titration up toan adequate level is essential both to obtain positive results and avoidadverse effects. The recommended starting dose is 4.5 g divided into 2equal doses of 2.25 g, the first taken at bedtime and the second taken2.5 to 4 hours later. The starting dosage can be decreased to 3.0 g/dayor increased to as high as 9.0 g/day in increments of 1.5 g/day (0.75 gper dose). Two weeks are recommended between dosage adjustments tooptimize reduction of daytime symptoms and minimize side effects. Theideal dose will provide an effective eight hours of sleep but, at theend of eight hours, very little of the drug will remain in the patient'sbloodstream to affect the patient's wakefulness.

The requirement to take Xyrem© twice each night is a substantialinconvenience to narcolepsy patients. The patient must typically set analarm to take the second dose, which can interrupt ongoing productivesleep. Several efforts have been made to provide a once-nightly modifiedrelease dosage form of sodium oxybate, but none has yet receivedapproval from the United States Food and Drug Administration (“FDA”) orproven effective in the clinic.

One of the biggest drawbacks of these once-nightly formulations is thereduction in bioavailability that occurs when sodium oxybate isformulated in a modified release dosage form, as measured by the bloodconcentration/time area under the curve (“AUC”). U.S. 2012/0076865 A1 byAllphin et al. (“Allphin”), for example, conducted two separatecrossover bioavailability trials involving three separate modifiedrelease formulations and an immediate release solution, and reported thefollowing bioavailability results:

Cmax AUClast AUCinf λ_z (1/hr) T_(1/2) (hr) Tmax (hr)^(a) (ug/ml) (hr *ug/ml) (hr * ug/ml) Summary of PK Parameters for Treatments A, B, CTreatment A N 29 29 29 29 29 29 Mean 1.22 0.6 4.50 (0.5, 4.75) 130.79350.84 351.2 SD 0.27 0.13 31.52 116.74 116.74 CV % 21.93 22.61 24.133.27 33.24 Mean 1.19 0.58 127.3 333.33 333.72 Treatment B N 18 18 19 1919 18 Mean 0.62 1.22 2.00 (1.50, 5.00) 41.78 188.23 196.25 SD 0.16 0.4018.40 103.60 102.50 CV % 26.44 32.58 44.03 55.04 52.23 Mean 0.59 1.1738.46 163.80 173.33 Treatment C N 19 19 19 19 19 19 Mean 0.74 0.99 2.50(1.00, 5.00) 50.49 221.64 222.60 SD 0.16 0.23 15.83 106.85 106 80 CV %22.25 22 93 31.35 48.21 47.98 Mean 0.72 0.96 48.10 200.08 201.12 Summaryof OK Parameters for Treatments A, D, E Treatment A N 30 30 30 30 30 30Mean 1.08 0.71 4.50 (0.50, 5.50) 114.59 301.28 301.59 SD 0.31 0.27 27.91100.85 100.87 CV % 29.00 37.90 24.36 33.47 33.45 Mean 1.03 0.67 111.20285.47 285.79 Treatment D N 30 30 30 30 30 30 Mean 0.46 1.63 0.75 (0.50,2.50) 25.10 64.44 65.58 SD 0.14 0.47 7.33 20.36 20.26 CV % 30.27 29.0029.20 31.60 30.90 Mean 0.44 1.56 24.10 61.31 62.55 Treatment E N 30 3030 30 30 30 Mean 0.59 1.36 1.00 (0.50, 5.00) 59.52 242.30 243.80 SD 0.200.64 17.72 117.15 116.79 CV % 34.57 46.91 29.77 48.35 47.91 Mean 0.551.25 56.89 216.33 218.12 Treatment A: Two 3 g IR doses administered fourhours apart Treatment B: One 6 g CR dose administered at time zero (noIR component) Treatment C: One 6 g CR dose administered at time zero (noIR component) Treatment D: One 4 g dose including IR and CR fractionsadministered at time zero Treatment E: One 8 g dose including IR and CRfractions administered at time zero

As can be seen, mean AUC_(inf), which measures the total exposure of thebody to sodium oxybate for a given dose, was significantly less for thedoses having a modified release component when compared to the immediaterelease doses. Mean AUC_(inf) for Treatment B, which included the exactsame dose of sodium oxybate as Treatment A, was only 56% of the meanAUC_(inf) for Treatment A; mean AUC_(inf) for Treatment C, which alsoincluded the same dose of sodium oxybate as Treatment A, was only 63% ofthe mean AUC_(inf) for Treatment A; mean AUC_(inf) for Treatment E wasonly 81% of the mean AUC_(inf) of Treatment A, even though Treatment Edosed 2 g more of sodium oxybate than Treatment A, which, compared tosame dose, represented only 610% of the mean AUC_(inf) of Treatment A.Mean AUC_(inf) for Treatment D was only 22% of the mean AUC_(inf) ofTreatment A, although Treatment D dosed 2 g less of sodium oxybate thanTreatment A, which, compared to same dose, represented only 33% of themean AUC_(inf) of Treatment A. As shown in FIGS. 12 and 14 of U.S.2012/0076865 A1, Allphin's formulations also suffered from an excess ofsodium oxybate remaining in the bloodstream at 8 hours.

U.S. Pat. No. 8,193,211 to Liang et al. (“Liang”) reports even lowerbioavailability from his once-nightly formulations. Liang developedseveral enterically coated delayed release formulations of sodiumoxybate, and tested these formulations in dogs alongside an immediaterelease formulation to compare the relative pharmacokinetics (PK) ofthese formulations. The results of Liang's testing are reported below:

Mean GHB Concentrations (ug/mL) Period 1 2 3 4 Time Point (Hr) DR1-w/Acid DR1-No Acid IR DR2 0 0.00 0.00 0.00 0.00 0.5 0.00 0.00 116.04 0.001 0.00 4.76 248.27 1.53 2 4.99 11.62 195.51 32.52 3 26.31 31.88 117.56100.99 4 35.14 38.26 47.21 100.57 5 29.18 34.77 8.74 54.99 6 21.09 27.830.00 23.42 7 11.25 9.13 0.00 7.52 8 8.67 2.53 0.00 0.34 10 1.43 3.030.00 0.00 12 0.98 0.67 0.00 0.00 14 0.43 0.00 0.00 0.00 Tmax (Hr) 4.25.2 1.2 3.7 Cmax (ug/mL) 38.77 58.44 249.5 112.7 AUClast 134.3 162.6601.0 318.4 Rel BA 22% 27% 100% 53% DR1-w/ Acid: Two 1 g DR capsulesadministered at time zero DR1-No Acid: Two 1 g DR capsules administeredat time zero IR: Two 1 g IR capsules administered at time zero DR2: Two1 g DR capsules administered at time zero

As can be seen, by encapsulating the sodium oxybate in anenteric/delayed release coating, Liang decreased the AUC of the sodiumoxybate significantly. One of the formulations, DR1-w/Acid, had arelative bioavailability of only 22% compared to the immediate releasedosage form. DR2 had the greatest relative bioavailability, but stillonly 53% compared to the immediate release dosage form. One can easilycalculate that any of the envisioned combinations of immediate release(IR) components and delayed release (DR) components as described in col.5 lines 3 to 28 of U.S. Pat. No. 8,193,211 will not give a relativebioavailability greater than 78%.

All of these formulations are inconvenient for at least two reasons: (1)the low relative bioavailability necessitates an increase in the dosecompared to current IR treatments which already require a large dose(4.5 to 9 g a day), and (2) when provided in the form of pills, apatient must swallow around 4 to 9 pills per dose, which is a seriousinconvenience for the patient and potential drawback for patientcompliance.

Various other techniques are known for formulating modified releasedosage forms including, for example, the techniques described in U.S.Pat. No. 8,101,209 to Legrand et al. (“Legrand”). Legrand provides asystem ensuring that the active ingredient is released with certaintyfrom the modified release dosage form by means of a dual mechanism of“time-dependent” and “pH-dependent” release. Legrand did not describeany dosage forms for delivering sodium oxybate or other forms ofgamma-hydroxybutyrate.

Another drawback of Xyrem® is the high level of the daily dose,generally 7.5 g or 9 g of sodium oxybate taken daily over long periodsof time. This represents a very high sodium intake which is notrecommended in persons with high blood pressure, risk of cardiovasculardisease, stroke or coronary heart disease (See WHO. Guideline: Sodiumintake for adults and children. Geneva, World Health Organization (WHO),2012.).

Accordingly, one object of the present invention is to provide modifiedrelease formulations of gamma-hydroxybutyrate that are administered onlyonce at bed-time with improved dissolution and pharmacokinetic profiles.

Another object of the present invention is to provide modified releaseformulations of gamma-hydroxybutyrate that optimize the bioavailabilityof the gamma-hydroxybutyrate, and roughly approximate thebioavailability of an equal dose of an immediate release liquid solutionof sodium oxybate administered twice nightly.

Still another object of the present invention is to provide once-nightlymodified release formulations of gamma-hydroxybutyrate that roughlyapproximate or exceed the bioavailability of an equal dose of animmediate release solution of sodium oxybate administered twice nightly,across the entire therapeutic range of sodium oxybate doses.

Yet another object of the present invention is to provide modifiedrelease formulations of gamma-hydroxybutyrate which, 8 hours afteradministration, produce very little residual drug content in thebloodstream of most patients but still similar to the one observed afteradministration of an equal dose of an immediate release liquid solutionof sodium oxybate administered twice nightly.

Yet another object of the present invention is to improve thetherapeutic effectiveness and safety profile of gamma-hydroxybutyratebased on novel dissolution and pharmacokinetic profiles.

Yet another object of the present invention is to provide modifiedrelease formulations of gamma-hydroxybutyrate that yield a similarpharmacokinetic profile compared to an immediate release liquid solutionof sodium oxybate administered twice nightly while potentially giving areduced dose.

Yet another object of the present invention is to provide modifiedrelease formulations of gamma-hydroxybutyrate that allow once dailyadministration and reduced dose compared to the commercial treatmentXyrem®.

Yet another object of the present invention is to provide a convenientdosage form of gamma-hydroxybutyrate that may be easily swallowed.

Yet another object of the present invention is to provide modifiedrelease formulations of gamma-hydroxybutyrate that are administered onlyonce at bed-time with improved dissolution and pharmacokinetic profilesand reduced sodium content compared to an immediate release liquidsolution of sodium oxybate administered twice nightly.

SUMMARY OF INVENTION

As the prior art demonstrates, it is extremely difficult to find amodified release formulation of gamma-hydroxybutyrate which, whenadministered only once nightly, has a comparable bioavailability to animmediate release liquid solution of sodium oxybate administered twicenightly. Even if such a formulation could be found, it probably stillwould not be satisfactory because the dose of gamma-hydroxybutyratediffers among individuals, and the size of the dose affects the amountof drug absorbed through the GI tract. I.e., even if the prior artformulations achieved comparable bioavailability at one dose—which theydo not—they would not be comparable at other doses.

The inventors have discovered a novel relationship between the in vitrorelease profile of gamma-hydroxybutyrate modified release formulationsand in vivo absorption which permits, for the first time, a modifiedrelease formulation of gamma-hydroxybutyrate that approximates thebioavailability of a twice-nightly equipotent immediate release liquidsolution of sodium oxybate, and that does so across a range oftherapeutic doses. In particular, the inventors have discovered that amodified release formulation of gamma-hydroxybutyrate that rapidlyreleases half of its gamma-hydroxybutyrate in 0.1N hydrochloric aciddissolution medium, and rapidly releases the other half of itsgamma-hydroxybutyrate in phosphate buffer pH 6.8 dissolution medium,approximates or exceeds the in vivo bioavailability of an equipotentimmediate release liquid solution of sodium oxybate administered twicenightly. This can be seen by comparing the formulations of Examples 1and 4, which satisfy the dissolution requirements of the presentinvention and achieve the necessary bioavailability for a commercialformulation, with the Comparative formulation of Example 7, whichexhibited a dissolution profile similar to prior art dissolutionprofiles, and did not achieve the necessary bioavailability for acommercial formulation.

This phenomenon is observed especially with higher doses ofgamma-hydroxybutyrate. For example, the inventors have discovered that amodified release composition of gamma-hydroxybutyrate according to theinvention administered once approximately two hours after a standardizedevening meal at the dose equivalent to 7.5 g of sodium oxybate resultsin a similar pharmacokinetic profile as an immediate release liquidsolution of sodium oxybate given in two separate equal doses of 4.5 g ofsodium oxybate each administered at t₀ and t_(4h).

The modified release formulations of gamma-hydroxybutyrate preferablyhave both immediate release and modified release portions. The releaseof gamma-hydroxybutyrate from the immediate release portion ispractically uninhibited, and occurs almost immediately in 0.1Nhydrochloric acid dissolution medium. In contrast, while the modifiedrelease portion also preferably releases its gamma-hydroxybutyratealmost immediately when fully triggered, the release is not triggereduntil a predetermined lag-time or the drug is subjected to a suitabledissolution medium such as a phosphate buffer pH 6.8 dissolution medium.Without wishing to be bound by any theory, it is believed that thisrapid release in two dissolution media compresses the bloodconcentration vs. time curve in vivo, resulting in a relativebioavailability of gamma-hydroxybutyrate comparable to or greater thanan equipotent dose of an immediate-release liquid solution of sodiumoxybate administered twice nightly. In a first embodiment, providedherein is a method of treating cataplexy or excessive daytime sleepiness(EDS) in a patient with narcolepsy, the method comprising: orallyadministering a dosage of a composition comprising gamma-hydroxybutyrateonce per night, wherein the patient experiences fewer adverse reactionsas compared to a second patient administered twice-nightlygamma-hydroxybutyrate treatment.

In a second embodiment, provided herein is a method comprising: orallyadministering a dosage of a composition comprising gamma-hydroxybutyrateonce per night, wherein the patient experiences no adverse reactions.

In a third embodiment, provided herein is a method comprising: orallyadministering a dosage of a composition comprising gamma-hydroxybutyrateonce per night, wherein the patient experiences less or no obtundationas compared to the twice-nightly gamma-hydroxybutyrate treatment.

In a fourth embodiment, provided herein is a method comprising: orallyadministering a dosage of a composition comprising gamma-hydroxybutyrateonce per night, wherein the patient experiences less or no clinicallysignificant respiratory depression as compared to the twice-nightlygamma-hydroxybutyrate treatment.

In a fifth embodiment, provided herein is a method comprising: orallyadministering a dosage of a composition comprising gamma-hydroxybutyrateonce per night, wherein the patient does not have profound CNSdepression or severe difficulty breathing at doses of 4.5 g to 9 ggamma-hydroxybutyrate per night.

In a sixth embodiment, provided herein is a method comprising: orallyadministering a dosage of a composition comprising gamma-hydroxybutyrateonce per night, wherein the patient does not have a clinicallysignificant worsening of respiratory function as measured byapnea/hypopnea index and pulse oximetry at doses of 4.5 g to 9 ggamma-hydroxybutyrate per night.

In a seventh embodiment, provided herein is a method comprising: orallyadministering a dosage of a composition comprising gamma-hydroxybutyrateonce per night, wherein the patient has statistically significantimprovement on the Maintenance of Wakefulness Test at dosages of 6 g,7.5 g, and 9 g as compared to placebo. In some aspects, the patient hasa latency to sleep onset about 5 minutes or more than placebo.

In an eighth embodiment, provided herein is a method comprising: orallyadministering a dosage of a composition comprising gamma-hydroxybutyrateonce per night, wherein the patient has statistically significantimprovement on the Clinical Global Impression-Improvement at dosages of6 g, 7.5 g, and 9 g as compared to placebo. In some aspects, the patientis 5 times or more likely to respond as much or very much improved ascompared to placebo.

In a ninth embodiment, provided herein is a method comprising: orallyadministering a dosage of a composition comprising gamma-hydroxybutyrateonce per night, wherein the patient has statistically significantimprovement in mean weekly cataplexy attacks at dosages of 6 g, 7.5 g,and 9 g as compared to placebo. In some aspects, the patient has about 4or fewer mean cataplexy attacks per week as compared to placebo.

In a tenth embodiment, provided herein is a method comprising: orallyadministering a dosage of a composition comprising gamma-hydroxybutyrateonce per night, wherein a peak plasma concentration (C_(max)) followingadministration of one dose is lower than a twice-nightlygamma-hydroxybutyrate treatment. In some aspects, the C_(max) followingadministration of one 6 g dose is about 65.8 mcg/mL. In other aspects,there is a steady decrease in concentration following a time to peakplasma concentration (T_(max)) approximately two hours after dosing. Inadditional aspects, the T_(max) is about 1.51 hours.

In an eleventh embodiment, provided herein is a method comprising:orally administering a dosage of a composition comprisinggamma-hydroxybutyrate once per night, wherein the dosage of thecomposition initially administered comprises 4.5 ggamma-hydroxybutyrate. In some aspects, the method further comprisesincreasing the dosage by 1.5 g per night at weekly intervals to aneffective dosage range of 6 g to 9 g per night.

In a twelfth embodiment, provided herein is a method comprising: orallyadministering a dosage of a composition comprising gamma-hydroxybutyrateonce per night, wherein the composition is a powder for oral suspension.In some aspects, the composition comprises immediate-release andcontrolled-release granules comprising gamma-hydroxybutyrate and mayfurther comprise microcrystalline cellulose spheres, povidone K30,hydrogenated vegetable oil, methacrylic acid copolymer, malic acid,xanthan gum, hydroxyethyl cellulose, carrageenan, and/or magnesiumstearate.

In a thirteenth embodiment, provided herein is a method comprising:providing the composition in a nightly dose packet of 4.5 g, 6 g, 7.5,g, or 9 g gamma-hydroxybutyrate, wherein the composition is a powder fororal suspension; and orally administering a dosage of a compositioncomprising gamma-hydroxybutyrate once per night.

In a fourteenth embodiment, provided herein is a method comprising:providing the composition in a nightly dose packet of 4.5 g, 6 g, 7.5,g, or 9 g gamma-hydroxybutyrate, wherein the composition is a powder fororal suspension; preparing the dosage by suspending the composition fromthe dose packet in water; and orally administering a dosage of acomposition comprising gamma-hydroxybutyrate once per night. In someaspects, the dosage is suspended in approximately 50 mL of water.

In a fifteenth embodiment, provided herein is a method comprising:orally administering a dosage of a composition comprisinggamma-hydroxybutyrate once per night, wherein the dosage is administeredwithout regard for meals.

In a sixteenth embodiment, provided herein is a method comprising:orally administering a dosage of a composition comprisinggamma-hydroxybutyrate once per night, wherein the patient is in bedprior to orally administering the dosage. In some aspects, the patientlays down immediately after administering the dosage.

In a seventeenth embodiment, provided herein is a method comprising:orally administering a dosage of a composition comprisinggamma-hydroxybutyrate once per night, wherein the patient falls asleepwithin 5 minutes to 15 minutes after administering the dosage.

In an eighteenth embodiment, provided herein is a method comprising:orally administering a dosage of a composition comprisinggamma-hydroxybutyrate once per night and administering single dose ofdivalproex sodium ER. In some aspects, the dose of divalproex sodium ERis about 1250 mg.

In a nineteenth embodiment, provided herein is a method comprising:orally administering a dosage of a composition comprisinggamma-hydroxybutyrate once per night, wherein the patient is an adult.

In a twentieth embodiment, provided herein is a method of treatingcataplexy or excessive daytime sleepiness (EDS) in a patient withnarcolepsy, the method comprising: orally administering a dosage of acomposition comprising gamma-hydroxybutyrate once per night, wherein thepatient experiences less obtundation as compared to a twice-nightlygamma-hydroxybutyrate treatment.

In a twenty first embodiment, provided herein is a method comprising:orally administering a dosage of a composition comprisinggamma-hydroxybutyrate once per night, wherein the patient experiences noobtundation.

In a twenty second embodiment, provided herein is a method comprising:orally administering a dosage of a composition comprisinggamma-hydroxybutyrate once per night, wherein the patient experiencesless or no clinically significant respiratory depression as compared tothe twice-nightly gamma-hydroxybutyrate treatment.

In a twenty third embodiment, provided herein is a method comprising:orally administering a dosage of a composition comprisinggamma-hydroxybutyrate once per night, wherein the patient does not haveprofound CNS depression or severe difficulty breathing at doses of 4.5 gto 9 g gamma-hydroxybutyrate per night.

In a twenty fourth embodiment, provided herein is a method comprising:orally administering a dosage of a composition comprisinggamma-hydroxybutyrate once per night, wherein the patient does not havea clinically significant worsening of respiratory function as measuredby apnea/hypopnea index and pulse oximetry at doses of 4.5 g to 9 ggamma-hydroxybutyrate per night.

In a twenty fifth embodiment, provided herein is a method comprising:orally administering a dosage of a composition comprisinggamma-hydroxybutyrate once per night, wherein the patient hasstatistically significant improvement on the Maintenance of WakefulnessTest at dosages of 6 g, 7.5 g, and 9 g as compared to placebo. In someaspects, the patient has a latency to sleep onset about 5 minutes ormore than placebo.

In a twenty sixth embodiment, provided herein is a method comprising:orally administering a dosage of a composition comprisinggamma-hydroxybutyrate once per night, wherein the patient hasstatistically significant improvement on the Clinical GlobalImpression-Improvement at dosages of 6 g, 7.5 g, and 9 g as compared toplacebo. In some aspects, the patient is 5 times or more likely torespond as much or very much improved as compared to placebo.

In a twenty seventh embodiment, provided herein is a method comprising:orally administering a dosage of a composition comprisinggamma-hydroxybutyrate once per night, wherein the patient hasstatistically significant improvement in mean weekly cataplexy attacksat dosages of 6 g, 7.5 g, and 9 g as compared to placebo. In someaspects, the patient has about 4 or fewer mean cataplexy attacks perweek as compared to placebo.

In a twenty ninth embodiment, provided herein is a method of treatingcataplexy or excessive daytime sleepiness (EDS) in a patient withnarcolepsy, the method comprising: orally administering a dosage of acomposition comprising gamma-hydroxybutyrate once per night, wherein thepatient experiences less respiratory depression as compared to atwice-nightly gamma-hydroxybutyrate treatment.

In a thirtieth embodiment, provided herein is a method comprising:orally administering a dosage of a composition comprisinggamma-hydroxybutyrate once per night, wherein the patient experiences noclinically significant respiratory depression.

In a thirty first embodiment, provided herein is a method comprising:orally administering a dosage of a composition comprisinggamma-hydroxybutyrate once per night, wherein the patient experiencesless or no obtundation as compared to the twice-nightlygamma-hydroxybutyrate treatment.

In a thirty second embodiment, provided herein is a method comprising:orally administering a dosage of a composition comprisinggamma-hydroxybutyrate once per night, wherein the patient does not haveprofound CNS depression or severe difficulty breathing at doses of 4.5 gto 9 g gamma-hydroxybutyrate per night.

In a thirty third embodiment, provided herein is a method comprising:orally administering a dosage of a composition comprisinggamma-hydroxybutyrate once per night, wherein the patient does not havea clinically significant worsening of respiratory function as measuredby apnea/hypopnea index and pulse oximetry at doses of 4.5 g to 9 ggamma-hydroxybutyrate per night.

In a thirty fourth embodiment, provided herein is a method comprising:orally administering a dosage of a composition comprisinggamma-hydroxybutyrate once per night, wherein the patient hasstatistically significant improvement on the Maintenance of WakefulnessTest at dosages of 6 g, 7.5 g, and 9 g as compared to placebo. In someaspects, the patient has a latency to sleep onset about 5 minutes ormore than placebo.

In a thirty fifth embodiment, provided herein is a method comprising:orally administering a dosage of a composition comprisinggamma-hydroxybutyrate once per night, wherein the patient hasstatistically significant improvement on the Clinical GlobalImpression-Improvement at dosages of 6 g, 7.5 g, and 9 g as compared toplacebo. In some aspects, the patient is 5 times or more likely torespond as much or very much improved as compared to placebo.

In a thirty sixth embodiment, provided herein is a method comprising:orally administering a dosage of a composition comprisinggamma-hydroxybutyrate once per night, wherein the patient hasstatistically significant improvement in mean weekly cataplexy attacksat dosages of 6 g, 7.5 g, and 9 g as compared to placebo. In someaspects, the patient has about 4 or fewer mean cataplexy attacks perweek as compared to placebo.

In a thirty seventh embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the modified release formulation issuitable for administration only once nightly, without obtundation andclinically significant respiratory depression occurring in adultpatients treated with twice-nightly gamma-hydroxybutyrate.

In a thirty eighth embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the modified release formulation issuitable for administration only once nightly, with reduced side effectsof obtundation and clinically significant respiratory depressionoccurring in adult patients treated with twice-nightlygamma-hydroxybutyrate.

In a thirty ninth embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the immediate release portioncomprises gamma-hydroxybutyrate, and the modified release portioncomprises gamma-hydroxybutyrate coated with a coating comprising: apolymer carrying free carboxylic groups, and a hydrophobic compoundhaving a melting point equal or greater than 40° C.

In a fortieth embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the formulation yields a plasmaconcentration versus time curve when administered at a dose of 4.5 g,6.0 g or 7.5 g approximately two hours after a standardized evening mealsubstantially as depicted in FIG. 12 or FIG. 13 for the correspondingdose.

In a forty fourth embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the formulation yields a plasmaconcentration versus time curve when administered at a dose of 4.5 gapproximately two hours after a standardized evening meal substantiallyas depicted in FIG. 22 .

In a forty fifth embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the formulation yields a dissolutionprofile substantially as depicted in FIG. 7 and FIG. 8 .

In a forty sixth embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the formulation yields a dissolutionprofile substantially as depicted in FIG. 20 and FIG. 21 .

In a forty seventh embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the modified release portion yields adissolution profile substantially as depicted in FIG. 3 or FIG. 16 .

In a forty eighth embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the formulation yields a dissolutionprofile between the minimum and maximum values depicted in FIG. 25 andFIG. 26 .

In a forty ninth embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the formulation yields a dissolutionprofile between the minimum and maximum values depicted in FIG. 27 andFIG. 28 .

In a fiftieth embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the formulation yields a dissolutionprofile substantially as shown in any one of FIGS. 29 through 89 .

In a fifty first embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the formulation yields a plasmaconcentration versus time curve when administered at a dose of 4.5 g,7.5 g or 9.0 g approximately two hours after a standardized evening mealsubstantially as depicted in FIG. 90 for the corresponding dose.

In a fifty second embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the formulation yields a dissolutionprofile between the minimum and maximum values depicted in FIG. 26 andFIG. 28 .

In a fifty third embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the formulation is defined based onthe concentration of gamma-hydroxybutyrate in the blood stream 8 hoursafter administration to a patient, and further wherein a 4.5 g doseachieves a mean C_(8h) of from 4.7 to 9.0 microgram/mL.

In a fifty fourth embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the formulation is defined based onthe concentration of gamma-hydroxybutyrate in the blood stream 8 hoursafter administration to a patient, and further wherein a 4.5 g doseachieves a mean C_(8h) of from 3.5 to 4.7 microgram/mL.

In a fifty fifth embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the formulation is defined based onthe concentration of gamma-hydroxybutyrate in the blood stream 8 hoursafter administration to a patient, and further wherein a 6.0 g doseachieves a mean C_(8h) of from 6.3 to 16.7 microgram/mL.

In a fifty sixth embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the formulation is defined based onthe concentration of gamma-hydroxybutyrate in the blood stream 8 hoursafter administration to a patient, and further wherein a 6.0 g doseachieves a mean C_(8h) of from 7.3 to 15.4 microgram/mL.

In a fifty seventh embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the formulation is defined based onthe concentration of gamma-hydroxybutyrate in the blood stream 8 hoursafter administration to a patient, and further wherein a 7.5 g doseachieves a mean C_(8h) of from 13.0 to 40.3 microgram/mL.

In a fifty eighth embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the formulation is defined based onthe concentration of gamma-hydroxybutyrate in the blood stream 8 hoursafter administration to a patient, and further wherein a 7.5 g doseachieves a mean C_(8h) of from 24.7 to 37.2 microgram/mL.

In a fifty ninth embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the formulation is defined based onthe time required to reach maximum blood concentration ofgamma-hydroxybutyrate to a patient, and further achieves a medianT_(max) of 1.25 to 3.25 hours when administered once approximately twohours after a standardized evening meal.

In a sixtieth embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the formulation is defined based onthe time required to reach maximum blood concentration ofgamma-hydroxybutyrate to a patient, and further achieves a medianT_(max) of 0.5 to 3.25 hours when administered once approximately twohours after a standardized evening meal.

In a sixty first embodiment, provided herein is a modified releaseformulation of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the formulation produces a residualdrug content in the bloodstream similar to one observed afteradministration of an equal dose of an immediate release liquid solutionof gamma-hydroxybutyrate administered twice nightly.

In a sixty second embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation is suitable foradministration once-daily, and further wherein the formulation isresistant to alcohol-induced dose dumping.

In a sixty third embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation releases at least 80% ofits gamma-hydroxybutyrate at three hours when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasicpotassium phosphate buffer pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm, and further wherein ethanol concentrations fromabout 5% to about 20% does not change the dissolution profile.

In a sixty fourth embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation releases at least 80% ofits gamma-hydroxybutyrate at three hours when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasicpotassium phosphate buffer pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm, and further wherein ethanol concentrations fromabout 5% to about 20% does not change the dissolution profile.

In a sixty fifth embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation releases from 10% to 65%,of its gamma-hydroxybutyrate at one hour and three hours when tested ina dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm, and further wherein ethanol concentrations from about 5% to about20% does not change the dissolution profile.

In a sixty sixth embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the modified release portion releasesgreater than 80% of its gamma-hydroxybutyrate at three hours when testedin a dissolution apparatus 2 according to USP 38 <711> in 900 mL of0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm, and further wherein ethanolconcentrations from about 5% to about 20% does not change thedissolution profile.

In a sixty seventh embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the modified release portion releases lessthan 20% of its gamma-hydroxybutyrate at one hour when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm, and further wherein ethanol concentrations from about 5% to about20% does not change the dissolution profile.

In a sixty eighth embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the modified release portion provides amodified release profile, and the release rate when measured using afirst in vitro dissolution test in the absence of ethanol and therelease rate when using a second vitro dissolution test in the presenceof about 5% to about 20% ethanol (v/v) are substantially the same,wherein, other than the absence or presence ethanol, the first in vitrodissolution test and the second in vitro dissolution test are the same.

In a sixty ninth embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the modified release portion releasesgreater than 80% of its gamma-hydroxybutyrate at three hours in adissolution test started in 750 mL of 0.1N hydrochloric acid for 2 hoursthen switched to 950 mL 0.05M monobasic potassium phosphate bufferadjusted to pH 6.8 at a temperature of 37° C. and a paddle speed of 75rpm, and further wherein ethanol concentrations from about 5% to about20% does not change the dissolution profile.

In a seventieth embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the immediate release portion releasesgreater than 80% of its gamma-hydroxybutyrate at one hour when tested ina dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm, and further wherein ethanol concentrations from about 5% to about20% does not change the dissolution profile.

In a seventy first embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a dose of the formulation achieves arelative bioavailability (RBA) of greater than 80% when compared to anequal dose of an immediate release liquid solution ofgamma-hydroxybutyrate administered at t₀ and t_(4h) in equally divideddoses, when administered approximately two hours after a standardizedevening meal.

In a seventy second embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a dose of the formulation achieves a medianT_(max) of 1.25 to 3.25 hours when administered once approximately twohours after a standardized evening meal.

In a seventy third embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a dose of the formulation achieves a medianT_(max) of 0.5 to 3.25 hours when administered once approximately twohours after a standardized evening meal.

In a seventy fourth embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a dose of the formulation achieves a medianT_(max) of about 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, or 3.25 hourswhen administered once approximately two hours after a standardizedevening meal.

In a seventy fifth embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 7.5 g dose of the formulation achieves amean AUC_(inf) of greater than 300 hr·microgram/mL when administeredonce approximately two hours after a standardized evening meal. In someaspects, the mean AUC_(inf) is greater than 340 hr·microgram/mL, 375hr·microgram/mL, or greater than 400 hr·microgram/mL.

In a seventy sixth embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 7.5 g dose of the formulation achieves amean C_(max) of greater than 70 microgram/mL when administered onceapproximately two hours after a standardized evening meal.

In a seventy seventh embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a dose of the formulation achieves a meanAUC_(inf) of greater than 80% of the mean AUC_(inf) provided by an equaldose of immediate release liquid solution of gamma-hydroxybutyrateadministered at t₀ and t_(4h) in equally divided doses approximately twohours after a standardized evening meal, and a mean C_(8h) less than 95%of the mean C_(8h) provided by an equal dose of immediate release liquidsolution of gamma-hydroxybutyrate administered at t₀ and t_(4h) inequally divided doses approximately two hours after a standardizedevening meal.

In a seventy eighth embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 4.5 g dose achieves a mean C_(8h) of from4.7 to 9.0 microgram/mL when administered once approximately two hoursafter a standardized evening meal.

In a seventy ninth embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 4.5 g dose achieves a mean C_(8h) of from3.5 to 4.7 microgram/mL when administered once approximately two hoursafter a standardized evening meal.

In an eightieth embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 6.0 g dose achieves a mean C_(8h) of from6.3 to 16.7 microgram/mL when administered once approximately two hoursafter a standardized evening meal.

In an eighty first embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 6.0 g dose achieves a mean C_(8h) of from7.3 to 15.4 microgram/mL when administered once approximately two hoursafter a standardized evening meal.

In an eighty second embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 7.5 g dose achieves a mean C_(8h) of from13.0 to 40.3 microgram/mL when administered once approximately two hoursafter a standardized evening meal.

In an eighty third embodiment, provided herein is a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 7.5 g dose achieves a mean C_(8h) of from24.7 to 37.2 microgram/mL when administered once approximately two hoursafter a standardized evening meal.

In an eighty fourth embodiment, provided herein is a formulationcomprising: a modified release portion comprising: a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and at least one coating onthe gamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C.

In an eighty fifth embodiment, provided herein is a formulationcomprising: a modified release portion comprising: a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and at least one coating onthe gamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the weight ratio of the hydrophobiccompound to the polymer carrying free carboxylic groups is from 0.4 to4.

In an eighty sixth embodiment, provided herein is a formulationcomprising: a modified release portion comprising: a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and at least one coating onthe gamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the pharmaceutically acceptable salt ofgamma-hydroxybutyrate comprises a sodium salt of gamma-hydroxybutyricacid, a calcium salt of gamma-hydroxybutyric acid, a potassium salt ofgamma-hydroxybutyric acid, and/or a magnesium salt ofgamma-hydroxybutyric acid. In some aspects, the pharmaceuticallyacceptable salt of gamma-hydroxybutyrate is a calcium salt ofgamma-hydroxybutyric acid.

In an eighty seventh embodiment, provided herein is a formulationcomprising: a modified release portion comprising: a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and at least one coating onthe gamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., further comprising microcrystalline cellulose. Insome aspects, the microcrystalline cellulose is present at about 10%w/w-15% w/w.

In an eighty eighth embodiment, provided herein is a formulationcomprising: a modified release portion comprising: a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and at least one coating onthe gamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., further comprising a layer of hydroxypropylcellulose.

In an eighty ninth embodiment, provided herein is a formulationcomprising: a modified release portion comprising: a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and at least one coating onthe gamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the polymer carrying free carboxylic groupshas a pH-dependent solubility.

In a ninetieth embodiment, provided herein is a formulation comprising:a modified release portion comprising: a pharmaceutically acceptablesalt of gamma-hydroxybutyrate; and at least one coating on thegamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the polymer carrying free carboxylic groupsis selected from the group consisting of (meth)acrylic acid/alkyl(meth)acrylate copolymers, methacrylic acid and methylmethacrylatecopolymers, methacrylic acid and ethyl acrylate copolymers, methacrylicacid copolymers type A, B or C, cellulose derivatives carrying freecarboxylic groups, preferably cellulose acetate phthalate, celluloseacetate succinate, hydroxypropyl methyl cellulose phthalate,carboxymethylethyl cellulose, cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetatephthalate, zein, shellac, alginate, and mixtures thereof.

In a ninety first embodiment, provided herein is a formulationcomprising: a modified release portion comprising: a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and at least one coating onthe gamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the polymer carrying free carboxylic groupscomprises a methacrylic acid copolymer. In some aspects, the methacrylicacid copolymer is selected from the group consisting of poly(methacrylic acid, methyl methacrylate) 1:1, poly (methacrylic acid,ethyl acrylate) 1:1, poly (methacrylic acid, methyl methacrylate) 1:2,and mixtures thereof. In additional aspects, the methacrylic acidcopolymer comprises poly(methacrylic acid, ethyl acrylate) 1:1.

In a ninety second embodiment, provided herein is a formulationcomprising: a modified release portion comprising: a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and at least one coating onthe gamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the coating is from 10 to 50% of the weightof the modified release portion.

In a ninety third embodiment, provided herein is a formulationcomprising: a modified release portion comprising: a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and at least one coating onthe gamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., further comprising an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate.In some aspects, the formulation further comprises xanthan gum,carrageenan gum, gellan gum, guar gum, sodium alginate, calciumalginate, agar, sodium carboxymethyl cellulose, microcrystallinecellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ormixtures thereof. In at least one aspect, the formulation comprises guargum. For example, the guar gum is present at 1% to 15% by weight of theformulation.

In a ninety fourth embodiment, provided herein is a formulationcomprising: a modified release portion comprising: a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and at least one coating onthe gamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation is a dry particulateformulation or a powdered formulation.

In a ninety fifth embodiment, provided herein is a formulationcomprising: a modified release portion comprising: a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and at least one coating onthe gamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation comprises 4.5 g, 6.0 g, 7.5g, or 9.0 g of gamma-hydroxybutyrate.

In a ninety sixth embodiment, provided herein is a formulationcomprising: a modified release portion comprising: a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and at least one coating onthe gamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation is suitable to be orallyadministered once-nightly.

In a ninety seventh embodiment, provided herein is a formulation ofgamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C.

In a ninety eighth embodiment, provided herein is a formulation ofgamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the weight ratio of the hydrophobiccompound to the methacrylic acid copolymer is from 0.4 to 4.

In a ninety ninth embodiment, provided herein is a formulation ofgamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the ratio of gamma-hydroxybutyrate in theimmediate release portion and the modified release portion is from 10/90to 65/35.

In a one hundredth embodiment, provided herein is a formulation ofgamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the pharmaceutically acceptable salt ofgamma-hydroxybutyrate is selected from a sodium salt ofgamma-hydroxybutyric acid, a calcium salt of gamma-hydroxybutyric acid,a potassium salt of gamma-hydroxybutyric acid, and/or a magnesium saltof gamma-hydroxybutyric acid. In some aspects, the pharmaceuticallyacceptable salt of gamma-hydroxybutyrate is a calcium salt ofgamma-hydroxybutyric acid.

In a one hundred and first embodiment, provided herein is a formulationof gamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the microparticles further comprise a layerof hydroxypropyl cellulose.

In a one hundred and second embodiment, provided herein is a formulationof gamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the methacrylic acid copolymer is selectedfrom the group consisting of (meth)acrylic acid/alkyl (meth)acrylatecopolymers, methacrylic acid and methylmethacrylate copolymers,methacrylic acid and ethyl acrylate copolymers, methacrylic acidcopolymers type A, B or C, and mixtures thereof. In some aspects, themethacrylic acid copolymer is selected from the group consisting of poly(methacrylic acid, methyl methacrylate) 1:1, poly (methacrylic acid,ethyl acrylate) 1:1, poly (methacrylic acid, methyl methacrylate) 1:2,and mixtures thereof. In at least one aspect, the methacrylic acidcopolymers comprise poly(methacrylic acid, ethyl acrylate) 1:1.

In a one hundred and third embodiment, provided herein is a formulationof gamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the coating is from 10 to 50% of the weightof the microparticles.

In a one hundred and fourth embodiment, provided herein is a formulationof gamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., further comprising xanthan gum, carrageenan gum,gellan gum, guar gum, sodium alginate, calcium alginate, agar, sodiumcarboxymethyl cellulose, microcrystalline cellulose, hydroxyethylcellulose, hydroxypropylmethyl cellulose, or mixtures thereof. In someaspects, the formulation comprises guar gum. In at least one aspect, theguar gum is present at 1% to 15% by weight of the formulation.

In a one hundred and fifth embodiment, provided herein is a formulationof gamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation is a dry particulateformulation or a powdered formulation.

In a one hundred and sixth embodiment, provided herein is a formulationof gamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation comprises 4.5 g, 6.0 g, 7.5g, or 9.0 g of the pharmaceutically acceptable salt ofgamma-hydroxybutyrate.

In a one hundred and seventh embodiment, provided herein is aformulation of gamma-hydroxybutyrate comprising: an immediate releaseportion comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate; a modified release portion comprising:microparticles comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid copolymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein theformulation is suitable to be orally administered once-daily. In someaspects, the formulation is suitable to be orally administeredonce-nightly.

In a one hundred and eighth embodiment, provided herein is a formulationcomprising: a modified release portion comprising: microparticlescomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and at least one coating on the microparticles comprising a methacrylicacid copolymer.

In a one hundred and ninth embodiment, provided herein is a formulationcomprising: a modified release portion comprising: microparticlescomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and at least one coating on the microparticles comprising a methacrylicacid copolymer, wherein the pharmaceutically acceptable salt ofgamma-hydroxybutyrate is selected from a sodium salt ofgamma-hydroxybutyric acid, a calcium salt of gamma-hydroxybutyric acid,a potassium salt of gamma-hydroxybutyric acid, and/or a magnesium saltof gamma-hydroxybutyric acid. In some aspects, the pharmaceuticallyacceptable salt of gamma-hydroxybutyrate is a calcium salt ofgamma-hydroxybutyric acid.

In a one hundred and tenth embodiment, provided herein is a formulationcomprising: a modified release portion comprising: microparticlescomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and at least one coating on the microparticles comprising a methacrylicacid copolymer, wherein the microparticles further comprise a layer ofhydroxypropyl cellulose.

In a one hundred and eleventh embodiment, provided herein is aformulation comprising: a modified release portion comprising:microparticles comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate; and at least one coating on the microparticlescomprising a methacrylic acid copolymer, wherein the methacrylic acidcopolymer is selected from the group consisting of (meth)acrylicacid/alkyl (meth)acrylate copolymers, methacrylic acid andmethylmethacrylate copolymers, methacrylic acid and ethyl acrylatecopolymers, methacrylic acid copolymers type A, B or C, and mixturesthereof. In some aspects, the methacrylic acid copolymer is selectedfrom the group consisting of poly (methacrylic acid, methylmethacrylate) 1:1, poly (methacrylic acid, ethyl acrylate) 1:1, poly(methacrylic acid, methyl methacrylate) 1:2, and mixtures thereof. In atleast one aspect, the methacrylic acid copolymers comprisepoly(methacrylic acid, ethyl acrylate) 1:1.

In a one hundred and twelfth embodiment, provided herein is aformulation comprising: a modified release portion comprising:microparticles comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate; and at least one coating on the microparticlescomprising a methacrylic acid copolymer, wherein the coating is from 10to 50% of the weight of the microparticles.

In a one hundred and thirteenth embodiment, provided herein is a methodof treating cataplexy in narcolepsy or excessive daytime sleepiness(“EDS”) in narcolepsy, the method comprising administering a formulationof gamma-hydroxybutyrate once-daily.

In a one hundred and fourteenth embodiment, provided herein is a methodof treating cataplexy in narcolepsy or excessive daytime sleepiness(“EDS”) in narcolepsy, the method comprising administering a formulationof gamma-hydroxybutyrate once-nightly.

In a one hundred and fifteenth embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation is suitable foradministration once-daily.

In a one hundred and sixteenth embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation releases at least 80% ofits gamma-hydroxybutyrate at three hours when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasicpotassium phosphate buffer pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm.

In a one hundred and seventeenth embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation releases from 10% to 65%,of its gamma-hydroxybutyrate at one hour and three hours when tested ina dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm.

In a one hundred and eighteenth embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the modified release portion releasesgreater than 80% of its gamma-hydroxybutyrate at three hours when testedin a dissolution apparatus 2 according to USP 38 <711> in 900 mL of0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm.

In a one hundred and nineteenth embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the modified release portion releases lessthan 20% of its gamma-hydroxybutyrate at one hour when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm.

In a one hundred and twentieth embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the modified release portion releasesgreater than 80% of its gamma-hydroxybutyrate at three hours in adissolution test started in 750 mL of 0.1N hydrochloric acid for 2 hoursthen switched to 950 mL 0.05M monobasic potassium phosphate bufferadjusted to pH 6.8 at a temperature of 37° C. and a paddle speed of 75rpm.

In a one hundred and twenty first embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the immediate release portion releasesgreater than 80% of its gamma-hydroxybutyrate at one hour when tested ina dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm.

In a one hundred and twenty second embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a dose of the formulation achieves arelative bioavailability (RBA) of greater than 80% when compared to anequal dose of an immediate release liquid solution ofgamma-hydroxybutyrate administered at t₀ and t_(4h) in equally divideddoses, when administered approximately two hours after a standardizedevening meal.

In a one hundred and twenty third embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a dose of the formulation achieves a medianT_(max) of 1.25 to 3.25 hours when administered once approximately twohours after a standardized evening meal.

In a one hundred and twenty fourth embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a dose of the formulation achieves a medianT_(max) of 0.5 to 3.25 hours when administered once approximately twohours after a standardized evening meal.

In a one hundred and twenty fifth embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a dose of the formulation achieves a medianT_(max) of about 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, or 3.25 hourswhen administered once approximately two hours after a standardizedevening meal.

In a one hundred and twenty sixth embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 7.5 g dose of the formulation achieves amean AUC_(inf) of greater than 300 hr·microgram/mL when administeredonce approximately two hours after a standardized evening meal. In someaspects, the mean AUC_(inf) is greater than 340 hr·microgram/mL, greaterthan 375 hr·microgram/mL, or greater than 400 hr·microgram/mL.

In a one hundred and twenty seventh embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 7.5 g dose of the formulation achieves amean C_(max) of greater than 70 microgram/mL when administered onceapproximately two hours after a standardized evening meal.

In a one hundred and twenty eighth embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a dose of the formulation achieves a meanAUC_(inf) of greater than 80% of the mean AUC_(inf) provided by an equaldose of immediate release liquid solution of gamma-hydroxybutyrateadministered at t₀ and t_(4h) in equally divided doses approximately twohours after a standardized evening meal, and a mean C_(8h) less than 95%of the mean C_(8h) provided by an equal dose of immediate release liquidsolution of gamma-hydroxybutyrate administered at t₀ and t_(4h) inequally divided doses approximately two hours after a standardizedevening meal.

In a one hundred and twenty ninth embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 4.5 g dose achieves a mean C_(8h) of from4.7 to 9.0 microgram/mL when administered once approximately two hoursafter a standardized evening meal.

In a one hundred and thirtieth embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 4.5 g dose achieves a mean C_(8h) of from3.5 to 4.7 microgram/mL when administered once approximately two hoursafter a standardized evening meal.

In a one hundred and thirty first embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 6.0 g dose achieves a mean C_(8h) of from6.3 to 16.7 microgram/mL when administered once approximately two hoursafter a standardized evening meal.

In a one hundred and thirty second embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 6.0 g dose achieves a mean C_(8h) of from7.3 to 15.4 microgram/mL when administered once approximately two hoursafter a standardized evening meal.

In a one hundred and thirty third embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 7.5 g dose achieves a mean C_(8h) of from13.0 to 40.3 microgram/mL when administered once approximately two hoursafter a standardized evening meal.

In a one hundred and thirty fourth embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 7.5 g dose achieves a mean C_(8h) of from24.7 to 37.2 microgram/mL when administered once approximately two hoursafter a standardized evening meal.

In a one hundred and thirty fifth embodiment, provided herein is apharmaceutical formulation comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;and a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the composition produces a residual drugcontent in the bloodstream similar to one observed after administrationof an equal dose of an immediate release liquid solution ofgamma-hydroxybutyrate administered twice nightly.

In a one hundred and thirty sixth embodiment, provided herein is aformulation comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate in an immediate release portion and a modifiedrelease portion, wherein the modified release portion comprisesmicroparticles having at least one coating comprising a methacrylic acidcopolymer, and wherein the formulation is suitable for administrationonce-daily.

In a one hundred and thirty seventh embodiment, provided herein is aformulation comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate in an immediate release portion and a modifiedrelease portion, wherein the modified release portion comprisesmicroparticles having at least one coating comprising a methacrylic acidcopolymer, wherein a dose of the formulation achieves a mean AUC_(inf)of greater than 80% of the mean AUC_(inf) provided by an equal dose ofimmediate release liquid solution of gamma-hydroxybutyrate administeredat t₀ and t_(4h) in equally divided doses approximately two hours aftera standardized evening meal. In some aspects, a 7.5 g dose of theformulation achieves a mean AUC_(inf) of greater than 340hr·microgram/mL, greater than 375 hr·microgram/mL, or greater than 400hr·microgram/mL.

In a one hundred and thirty eighth embodiment, provided herein is aformulation comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate in an immediate release portion and a modifiedrelease portion, wherein the modified release portion comprisesmicroparticles having at least one coating comprising a methacrylic acidcopolymer, wherein a dose of the formulation achieves a median T_(max)of 1.25 to 3.25 hours when administered once approximately two hoursafter a standardized evening meal.

In a one hundred and thirty ninth embodiment, provided herein is aformulation comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate in an immediate release portion and a modifiedrelease portion, wherein the modified release portion comprisesmicroparticles having at least one coating comprising a methacrylic acidcopolymer, wherein a dose of the formulation achieves a median T_(max)of 0.5 to 3.25 hours when administered once approximately two hoursafter a standardized evening meal.

In a one hundred and fortieth embodiment, provided herein is aformulation comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate in an immediate release portion and a modifiedrelease portion, wherein the modified release portion comprisesmicroparticles having at least one coating comprising a methacrylic acidcopolymer, wherein a dose of the formulation achieves a median T_(max)of about 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, or 3.25 hours whenadministered once approximately two hours after a standardized eveningmeal.

In a one hundred and forty first embodiment, provided herein is aformulation comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate in an immediate release portion and a modifiedrelease portion, wherein the modified release portion comprisesmicroparticles having at least one coating comprising a methacrylic acidcopolymer, wherein a 7.5 g dose of the formulation achieves a mean Cmaxof greater than 70 microgram/mL when administered once approximately twohours after a standardized evening meal.

In a one hundred and forty second embodiment, provided herein is aformulation comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate in an immediate release portion and a modifiedrelease portion, wherein the modified release portion comprisesmicroparticles having at least one coating comprising a methacrylic acidcopolymer, wherein a 4.5 g dose achieves a mean C_(8h) of from 4.7 to9.0 microgram/mL when administered once approximately two hours after astandardized evening meal.

In a one hundred and forty third embodiment, provided herein is aformulation comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate in an immediate release portion and a modifiedrelease portion, wherein the modified release portion comprisesmicroparticles having at least one coating comprising a methacrylic acidcopolymer, wherein a 4.5 g dose achieves a mean C_(8h) of from 3.5 to4.7 microgram/mL when administered once approximately two hours after astandardized evening meal.

In a one hundred and forty fourth embodiment, provided herein is aformulation comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate in an immediate release portion and a modifiedrelease portion, wherein the modified release portion comprisesmicroparticles having at least one coating comprising a methacrylic acidcopolymer, wherein a 6.0 g dose achieves a mean C_(8h) of from 6.3 to16.7 microgram/mL when administered once approximately two hours after astandardized evening meal.

In a one hundred and forty fifth embodiment, provided herein is aformulation comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate in an immediate release portion and a modifiedrelease portion, wherein the modified release portion comprisesmicroparticles having at least one coating comprising a methacrylic acidcopolymer, wherein a 6.0 g dose achieves a mean C_(8h) of from 7.3 to15.4 microgram/mL when administered once approximately two hours after astandardized evening meal.

In a one hundred and forty sixth embodiment, provided herein is aformulation comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate in an immediate release portion and a modifiedrelease portion, wherein the modified release portion comprisesmicroparticles having at least one coating comprising a methacrylic acidcopolymer, wherein a 7.5 g dose achieves a mean C_(8h) of from 13.0 to40.3 microgram/mL when administered once approximately two hours after astandardized evening meal.

In a one hundred and forty seventh embodiment, provided herein is aformulation comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate in an immediate release portion and a modifiedrelease portion, wherein the modified release portion comprisesmicroparticles having at least one coating comprising a methacrylic acidcopolymer, wherein a 7.5 g dose achieves a mean C_(8h) of from 24.7 to37.2 microgram/mL when administered once approximately two hours after astandardized evening meal.

In a one hundred and forty eighth embodiment, provided herein is aformulation comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate in an immediate release portion and a modifiedrelease portion, wherein the modified release portion comprisesmicroparticles having at least one coating comprising a methacrylic acidcopolymer, wherein the 7.5 g dose of the formulation achieves a meanC_(8h) from 50% to 130% of the mean C_(8h) provided by an equal dose ofan immediate release liquid solution of gamma-hydroxybutyrateadministered at t₀ and t_(4h) in equally divided doses approximately twohours after a standardized evening meal. In some aspects, the meanC_(8h) achieved by the formulation is from 60% to 90% of the mean C_(8h)provided by the immediate release liquid solution ofgamma-hydroxybutyrate.

In a one hundred and forty ninth embodiment, provided herein is aformulation comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate in an immediate release portion and a modifiedrelease portion, wherein the modified release portion comprisesmicroparticles having at least one coating comprising a methacrylic acidcopolymer, wherein a dose of the formulation achieves a relativebioavailability (RBA) of greater than 80% when compared to an equal doseof an immediate release liquid solution of gamma-hydroxybutyrateadministered at t₀ and t_(4h) in equally divided doses, whenadministered approximately two hours after a standardized evening meal.

In a one hundred and fiftieth embodiment, provided herein is aformulation comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate in an immediate release portion and a modifiedrelease portion, wherein the modified release portion comprisesmicroparticles having at least one coating comprising a methacrylic acidcopolymer, wherein the dose is a 4.5 g, 6 g, 7.5 g, or 9 g dose of theformulation.

In a one hundred and fifty first embodiment, provided herein is apharmaceutical formulation comprising: particles ofgamma-hydroxybutyrate comprising a core and a coating deposited on thecore, wherein the coating inhibits the release of gamma-hydroxybutyrate,and wherein the coating comprises a polymer that is selected frommethylmethacrylate polymers.

In a one hundred and fifty second embodiment, provided herein is apharmaceutical formulation comprising: particles ofgamma-hydroxybutyrate comprising a core and a coating deposited on thecore, wherein the coating inhibits the release of gamma-hydroxybutyrate,and wherein the coating comprises a polymer that is selected frommethylmethacrylate polymers, further comprising ethylcellulose ormicrocrystalline cellulose.

In a one hundred and fifty third embodiment, provided herein is apharmaceutical formulation comprising: particles ofgamma-hydroxybutyrate comprising a core and a coating deposited on thecore, wherein the coating inhibits the release of gamma-hydroxybutyrate,and wherein the coating comprises a polymer that is selected frommethylmethacrylate polymers, further comprising cellulose derivativescarrying free carboxylic groups.

In a one hundred and fifty fourth embodiment, provided herein is apharmaceutical formulation comprising: particles ofgamma-hydroxybutyrate comprising a core and a coating deposited on thecore, wherein the coating inhibits the release of gamma-hydroxybutyrate,and wherein the coating comprises a polymer that is selected frommethylmethacrylate polymers, further comprising cellulose acetatephthalate, cellulose acetate succinate, hydroxypropyl methyl cellulosephthalate, carboxymethylethyl cellulose, cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetatephthalate, zein, shellac, alginate, and mixtures thereof.

In a one hundred and fifty fifth embodiment, provided herein is apharmaceutical formulation comprising: particles ofgamma-hydroxybutyrate comprising a core and a coating deposited on thecore, wherein the coating inhibits the release of gamma-hydroxybutyrate,and wherein the coating comprises a polymer that is selected frommethylmethacrylate polymers comprising Eudragit™ L100, or Eudragit™L100-55, or Eudragit™ S100.

In a one hundred and fifty sixth embodiment, provided herein is apharmaceutical formulation comprising: particles ofgamma-hydroxybutyrate comprising a core and a coating deposited on thecore, wherein the coating inhibits the release of gamma-hydroxybutyrate,and wherein the coating comprises a polymer that is selected frommethylmethacrylate polymers, wherein the coating comprises ethylacrylate.

In a one hundred and fifty seventh embodiment, provided herein is apharmaceutical formulation comprising: particles ofgamma-hydroxybutyrate comprising a core and a coating deposited on thecore, wherein the coating inhibits the release of gamma-hydroxybutyrate,and wherein the coating comprises a polymer that is selected frommethylmethacrylate polymers comprising poly (methacrylic acid, methylmethacrylate) 1:1, poly (methacrylic acid, ethyl acrylate) 1:1, or poly(methacrylic acid, methyl methacrylate).

In a one hundred and fifty eighth embodiment, provided herein is apharmaceutical formulation comprising: particles ofgamma-hydroxybutyrate comprising a core and a coating deposited on thecore, wherein the coating inhibits the release of gamma-hydroxybutyrate,and wherein the coating comprises a polymer that is selected frommethylmethacrylate polymers, wherein the coating comprises a polymerthat is selected from methylmethacrylate polymers having a pH-dependentsolubility.

In a one hundred and fifty ninth embodiment, provided herein is apharmaceutical formulation comprising: particles ofgamma-hydroxybutyrate comprising a core and a coating deposited on thecore; and immediate release particles that release at least 80% or 90%of its gamma-hydroxybutyrate at 3 hours, 2 hours, 1 hour, 0.5 hours, or0.25 hours, wherein the coating inhibits the release ofgamma-hydroxybutyrate, and wherein the coating comprises a polymer thatis selected from methylmethacrylate polymers.

Formulations that achieve this improved bioavailability can be describedusing several different pharmacokinetic and in vitro dissolutionparameters. In a one hundred and sixtieth embodiment, the inventionprovides a modified release formulation of gamma-hydroxybutyrate,preferably comprising immediate release and modified release portions,wherein a 7.5 g dose of the formulation has been shown to achieve a meanAUCinf of greater than 340 hr×microgram/mL.

In a one hundred and sixty first embodiment, the invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions, wherein a7.5 g dose of the formulation has been shown to achieve a mean AUCinf ofgreater than 340 hr×microgram/mL, and a mean C_(8h) that is from 50% to130% of the mean C_(8h) provided by an equal dose of an immediaterelease liquid solution of sodium oxybate administered at t0 and t4 h inequally divided doses approximately two hours after a standardizedevening meal.

In a one hundred and sixty second embodiment, the invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions, wherein theformulation releases (a) at least 80% of its gamma-hydroxybutyrate at 3hours when tested in a dissolution apparatus 2 according to USP 38 <711>in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at atemperature of 37° C. and a paddle speed of 75 rpm, and (b) from 10% to65%, of its gamma-hydroxybutyrate at one hour and three hours whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speedof 75 rpm.

In a one hundred and sixty third embodiment, the invention provides amodified release formulation of gamma-hydroxybutyrate, comprisingimmediate release and modified release portions, wherein (a) theformulation releases at least 80% of its gamma-hydroxybutyrate at 3hours, when tested in a dissolution apparatus 2 according to USP 38<711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 ata temperature of 37° C. and a paddle speed of 75 rpm, (b) theformulation releases from 10% to 65%, of its gamma-hydroxybutyrate atone hour and three hours when tested in a dissolution apparatus 2according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm, and (c) the modifiedrelease portion releases greater than 80% of its gamma-hydroxybutyrateat 3 hours in a dissolution test started in 750 mL of 0.1N hydrochloricacid for 2 hours then switched to 950 mL 0.05M monobasic potassiumphosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm.

In a one hundred and sixty fourth embodiment, the invention provides amodified release formulation of gamma-hydroxybutyrate, comprisingimmediate release and modified release portions, wherein (a) theformulation releases at least 80% of its gamma-hydroxybutyrate at 3hours, when tested in a dissolution apparatus 2 according to USP 38<711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 ata temperature of 37° C. and a paddle speed of 75 rpm, (b) theformulation releases 10% to 65%, of its gamma-hydroxybutyrate at onehour and at three hours when tested in a dissolution apparatus 2according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm, (c) the formulationreleases greater than 60% of its gamma-hydroxybutyrate at 10 hours whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speedof 75 rpm, and (d) the modified release portion releases greater than80% of its gamma-hydroxybutyrate at 3 hours in a dissolution teststarted in 750 mL of 0.1N hydrochloric acid for 2 hours then switched to950 mL 0.05M monobasic potassium phosphate buffer adjusted to pH 6.8 ata temperature of 37° C. and a paddle speed of 75 rpm.

In a one hundred and sixty fifth embodiment, the invention provides amodified release formulation of gamma-hydroxybutyrate, comprisingimmediate release and modified release portions, wherein (a) a 7.5 gdose of the formulation has been shown to achieve a mean AUCinf ofgreater than 340 hr×microgram/mL, and a mean C8 h that is from 50% to130%, of the mean C8 h provided by an equal dose of an immediate releaseliquid solution of sodium oxybate administered at t0 and t4 h in equallydivided doses approximately two hours after a standardized evening meal,and (b) the formulation releases (i) at least 80% or 90% of itsgamma-hydroxybutyrate at 3 hours when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.05M monobasic potassiumphosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of75 rpm, and (ii) from 10% to 65%, of its gamma-hydroxybutyrate at onehour and three hours when tested in a dissolution apparatus 2 accordingto USP 38 <711> in 900 mL of 0.1N hydrochloric acid at a temperature of37° C. and a paddle speed of 75 rpm, and (c) the modified releaseportion releases greater than 80% of its gamma-hydroxybutyrate at 3hours in a dissolution test started in 750 mL of 0.1N hydrochloric acidfor 2 hours then switched to 950 mL 0.05M monobasic potassium phosphatebuffer adjusted to pH 6.8 at a temperature of 37° C. and a paddle speedof 75 rpm.

In a one hundred and sixty sixth embodiment, the invention provides amodified release formulation of gamma-hydroxybutyrate comprisingimmediate release and modified release portions, wherein: (a) saidimmediate release portion releases greater than 80% of itsgamma-hydroxybutyrate at one hour when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm; (b) said modifiedrelease portion releases less than 20% of its gamma-hydroxybutyrate atone hour when tested in a dissolution apparatus 2 according to USP 38<711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37° C. anda paddle speed of 75 rpm; and (c) said modified release portion releasesgreater than 80% of its gamma-hydroxybutyrate at three hours when testedin a dissolution apparatus 2 according to USP 38 <711> in 900 mL of0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm.

In a one hundred and sixty seventh embodiment, the invention provides amodified release formulation of gamma-hydroxybutyrate comprisingimmediate release and modified release portions, wherein: (a) saidimmediate release portion releases greater than 80% of itsgamma-hydroxybutyrate at one hour when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm; (b) said modifiedrelease portion releases less than 20% of its gamma-hydroxybutyrate atone hour when tested in a dissolution apparatus 2 according to USP 38<711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37° C. anda paddle speed of 75 rpm; (c) said modified release portion releasesgreater than 80% of its gamma-hydroxybutyrate at three hours when testedin a dissolution apparatus 2 according to USP 38 <711> in 900 mL of0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm; and (d) said modified releaseportion releases greater than 80% of its gamma-hydroxybutyrate at 3hours in a dissolution test started in 750 mL of 0.1N hydrochloric acidfor 2 hours then switched to 950 mL 0.05M monobasic potassium phosphatebuffer adjusted to pH 6.8 at a temperature of 37° C. and a paddle speedof 75 rpm.

In a one hundred and sixty eighth embodiment, the invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions, wherein 4.5g, 6 g, 7.5 g, and 9 g doses of the formulation have been shown toachieve a relative bioavailability (RBA) of greater than 80% whencompared to an equal dose of an immediate release liquid solution ofsodium oxybate administered at t0 and t4 h in equally divided doses,when administered approximately two hours after a standardized eveningmeal.

In a one hundred and sixty ninth embodiment, the invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions, wherein 4.5g and 9 g doses of the formulation have been shown to achieve a relativebioavailability (RBA) of greater than 80% when compared to an equal doseof an immediate release liquid solution of sodium oxybate administeredat t0 and t4 h in equally divided doses, when administered approximatelytwo hours after a standardized evening meal.

In a one hundred and seventieth embodiment, the invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions, that yieldsa plasma concentration versus time curve when administered once nightlyat a strength of 4.5 g, 6.0 g or 7.5 g approximately two hours after astandardized evening meal substantially as depicted in FIG. 12 or FIG.13 for the corresponding strength.

In a one hundred and seventy first embodiment, the invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions, that yieldsa plasma concentration versus time curve when administered once nightlyat a strength of 4.5 g approximately two hours after a standardizedevening meal substantially as depicted in FIG. 22 .

In a one hundred and seventy second embodiment, the invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions, that yieldsa dissolution profile substantially as depicted in FIG. 7 and FIG. 8 .

In a one hundred and seventy second embodiment, the invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions, that yieldsa dissolution profile substantially as depicted in FIG. 20 and FIG. 21 .

In a one hundred and seventy third embodiment, the invention provides amodified release formulation of gamma-hydroxybutyrate comprisingimmediate release and modified release portions, wherein said modifiedrelease portion yields a dissolution profile substantially as depictedin FIG. 3 or FIG. 16 .

In a one hundred and seventy fourth embodiment, the invention provides amodified release formulation of gamma-hydroxybutyrate, comprisingimmediate release and modified release portions that yields adissolution profile between the minimum and maximum values depicted inFIG. 25 and FIG. 26 .

In a one hundred and seventy fifth embodiment, the invention provides amodified release formulation of gamma-hydroxybutyrate, comprisingimmediate release and modified release portions that yields adissolution profile between the minimum and maximum values depicted inFIG. 27 and FIG. 28 .

In a one hundred and seventy sixth embodiment, the invention provides amodified release formulation of gamma-hydroxybutyrate yielding adissolution profile substantially as shown in any one of FIGS. 29through 89 .

In a one hundred and seventy seventh embodiment, the present inventionprovides a modified release formulation of gamma-hydroxybutyrate,preferably comprising immediate release and modified release portions,that yields a plasma concentration versus time curve when administeredonce nightly at a strength of 4.5 g, 7.5 g or 9.0 g approximately twohours after a standardized evening meal substantially as depicted inFIG. 90 for the corresponding strength.

In a one hundred and seventy eighth embodiment, the present inventionprovides a modified release formulation of gamma-hydroxybutyrate,preferably comprising immediate release and modified release portionsthat yields a dissolution profile between the minimum and maximum valuesdepicted in FIG. 26 and FIG. 28 .

In a one hundred and seventy ninth embodiment, the present inventionprovides a pharmaceutical composition storage and administration systemcomprising: at least seven nightly dose packets, each nightly dosepacket operable to contain a single once daily dosage of a compositioncomprising gamma-hydroxybutyrate; one or more packet containers, eachpacket container operable to receive up to seven nightly dose packets; amixing cup comprising a lid, a first fill line, and a second fill line;a mixing cup receptacle comprising a cup retaining portion operable toreceive the mixing cup; and a carton operable to removably receive theone or more packet containers with up to seven packets in each containerand the mixing cup receptacle with the mixing cup.

In a one hundred and eightieth embodiment, the present inventionprovides a pharmaceutical composition storage and administration system,wherein each nightly dose packet contains a once daily dosage of 4.5 g,6 g, 7.5, g, or 9 g gamma-hydroxybutyrate.

In a one hundred and eighty first embodiment, the present inventionprovides a pharmaceutical composition storage and administration system,wherein the carton is operable to removably receive one packet containerwith seven nightly dose packets and the mixing cup receptacle with themixing cup to provide a 7-day supply of the composition.

In a one hundred and eighty second embodiment, the present inventionprovides a pharmaceutical composition storage and administration system,wherein the mixing cup receptacle further comprises a packet portionoperable to receive up to two nightly dose packets. In some aspects, thecarton is operable to removable receive four packet containers, eachwith seven nightly dose packets, and the mixing cup receptacle with themixing cup to provide a 30-day supply of the composition.

In a one hundred and eighty third embodiment, the present inventionprovides a pharmaceutical composition storage and administration system,wherein the first fill line measures about 50 mL and the second fillline measures about 25 mL.

In a one hundred and eighty fourth embodiment, the present inventionprovides a pharmaceutical composition storage and administration system,wherein the mixing cup comprises a bottom and a wall having an innerside operable to intersect with the bottom. In some aspects, theintersection of the inner side of the wall and the bottom is rounded tolimit adhesion to the mixing cup. In other aspects, the intersection isnot 90 degrees.

In a one hundred and eighty fifth embodiment, the present inventionprovides a method of preparing and administering a pharmaceuticalcomposition to a patient, the method comprising: providing apharmaceutical composition storage and administration system; removingthe lid of the mixing cup and filling the mixing cup with water up tothe first fill line; opening one nightly dose packet; emptying thecomposition from the nightly dose packet into the mixing cup filled withwater; replacing the lid of the mixing cup; shaking the mixing cup toform a first suspension of the composition in the water; andadministering the first suspension to the patient.

In a one hundred and eighty sixth embodiment, the present inventionprovides a method of preparing and administering a pharmaceuticalcomposition to a patient, the method further comprising: removing thelid of the mixing cup and filling the mixing cup with water up to thesecond fill line; replacing the lid of the mixing cup; shaking themixing cup to form a second suspension of any residual composition inthe water; and administering the second suspension to the patient.

In a one hundred and eighty seventh embodiment, the present inventionprovides a once-daily modified release formulation ofgamma-hydroxybutyrate, wherein the formulation decreases the number ofcataplexy attacks (NCA), compared to a dosing regimen consisting ofadministering the twice-nightly gamma-hydroxybutyrate treatment.

In a one hundred and eighty eighth embodiment, the present inventionprovides a once-daily modified release formulation ofgamma-hydroxybutyrate, wherein the formulation produces less confusion,less depressive syndrome, less incontinence, less nausea, or lesssleepwalking, compared to a dosing regimen consisting of administeringthe twice-nightly gamma-hydroxybutyrate treatment.

In a one hundred and eighty ninth embodiment, the present inventionprovides a once-daily modified release formulation ofgamma-hydroxybutyrate, wherein the formulation decreases PSG transitionsfrom N/2 to N/3 and REM sleep to wake and N1 sleep, compared to a dosingregimen consisting of administering the twice-nightlygamma-hydroxybutyrate treatment.

In a one hundred and ninetieth embodiment, the present inventionprovides a once-daily modified release formulation ofgamma-hydroxybutyrate, wherein the formulation decreases the number ofarousals or wakenings obtained from a polysomnogram, compared to adosing regimen consisting of administering the twice-nightlygamma-hydroxybutyrate treatment.

In a one hundred and ninety first embodiment, the present inventionprovides a once-daily modified release formulation ofgamma-hydroxybutyrate, wherein the formulation decreases daytimesleepiness when measured by the Maintenance of Wakefulness Test based onEEG measures of wakefulness, compared to a dosing regimen consisting ofadministering the twice-nightly gamma-hydroxybutyrate treatment.

In a one hundred and ninety second embodiment, the present inventionprovides a once-daily modified release formulation ofgamma-hydroxybutyrate, wherein the formulation decreases the hypnagogichallucinations or sleep paralysis symptoms in Type 1 narcolepsypatients, compared to a dosing regimen consisting of administering thetwice-nightly gamma-hydroxybutyrate treatment.

In a one hundred and ninety third embodiment, the present inventionprovides a once-daily modified release formulation ofgamma-hydroxybutyrate, wherein the formulation increases the mean sleeplatency compared to a dosing regimen consisting of administering thetwice-nightly gamma-hydroxybutyrate treatment.

In a one hundred and ninety fourth embodiment, the present inventionprovides a once-daily modified release formulation ofgamma-hydroxybutyrate, wherein the formulation decreases excessivedaytime sleepiness (EDS) as measured by patient report via the EpworthSleepiness Scale (ESS), compared to a dosing regimen consisting ofadministering the twice-nightly gamma-hydroxybutyrate treatment.

In a one hundred and ninety fifth embodiment, the present inventionprovides a once-daily modified release formulation ofgamma-hydroxybutyrate, wherein the formulation improves a ClinicalGlobal Impression (CGI) rating of sleepiness, compared to a dosingregimen consisting of administering the twice-nightlygamma-hydroxybutyrate treatment.

In a one hundred and ninety sixth embodiment, the present inventionprovides a method of treating cataplexy or excessive daytime sleepiness(EDS) in a patient with narcolepsy by orally administering a dosage of acomposition comprising gamma-hydroxybutyrate once per night, wherein thepatient has a decrease in the number of cataplexy attacks (NCA),compared to a patient with a dosing regimen consisting of administeringthe twice-nightly gamma-hydroxybutyrate treatment.

In a one hundred and ninety seventh embodiment, the present inventionprovides a method of treating cataplexy or excessive daytime sleepiness(EDS) in a patient with narcolepsy by orally administering a dosage of acomposition comprising gamma-hydroxybutyrate once per night, wherein thepatient has less confusion, less depressive syndrome, less incontinence,less nausea, or less sleepwalking, compared to a patient with a dosingregimen consisting of administering the twice-nightlygamma-hydroxybutyrate treatment.

In a one hundred and ninety eighth embodiment, the present inventionprovides a method of treating cataplexy or excessive daytime sleepiness(EDS) in a patient with narcolepsy by orally administering a dosage of acomposition comprising gamma-hydroxybutyrate once per night, wherein thepatient has a decrease in PSG transitions from N/2 to N/3 and REM sleepto wake and N1 sleep, compared to a patient with a dosing regimenconsisting of administering the twice-nightly gamma-hydroxybutyratetreatment.

In a one hundred and ninety ninth embodiment, the present inventionprovides a method of treating cataplexy or excessive daytime sleepiness(EDS) in a patient with narcolepsy by orally administering a dosage of acomposition comprising gamma-hydroxybutyrate once per night, wherein thepatient has a decrease in the number of arousals or wakenings obtainedfrom a polysomnogram, compared to a patient with a dosing regimenconsisting of administering the twice-nightly gamma-hydroxybutyratetreatment.

In a two hundredth embodiment, the present invention provides a methodof treating cataplexy or excessive daytime sleepiness (EDS) in a patientwith narcolepsy by orally administering a dosage of a compositioncomprising gamma-hydroxybutyrate once per night, wherein the patient hasa decrease in hypnagogic hallucinations or sleep paralysis symptoms inType 1 narcolepsy patients, compared to a patient with a dosing regimenconsisting of administering the twice-nightly gamma-hydroxybutyratetreatment.

In a two hundred and first embodiment, the present invention provides amethod of treating cataplexy or excessive daytime sleepiness (EDS) in apatient with narcolepsy by orally administering a dosage of acomposition comprising gamma-hydroxybutyrate once per night, wherein thepatient has a decrease in daytime sleepiness when measured by theMaintenance of Wakefulness Test based on EEG measures of wakefulness,compared to a patient administered the twice-nightlygamma-hydroxybutyrate treatment.

In a two hundred and second embodiment, the present invention provides amethod of treating cataplexy or excessive daytime sleepiness (EDS) in apatient with narcolepsy by orally administering a dosage of acomposition comprising gamma-hydroxybutyrate once per night, wherein thepatient has a decrease in excessive daytime sleepiness (EDS) as measuredby patient report via the Epworth Sleepiness Scale (ESS), compared to apatient administered the twice-nightly gamma-hydroxybutyrate treatment.

In a two hundred and third embodiment, the present invention provides amethod of treating cataplexy or excessive daytime sleepiness (EDS) in apatient with narcolepsy by orally administering a dosage of acomposition comprising gamma-hydroxybutyrate once per night, wherein thepatient has an increase in mean sleep latency compared to a patientadministered the twice-nightly gamma-hydroxybutyrate treatment.

In a two hundred and fourth embodiment, the present invention provides amethod of treating cataplexy or excessive daytime sleepiness (EDS) in apatient with narcolepsy by orally administering a dosage of acomposition comprising gamma-hydroxybutyrate once per night, wherein thepatient improves the Clinical Global Impression-Improvement (CGI) ratingof sleepiness, compared to a patient administered the twice-nightlygamma-hydroxybutyrate treatment.

In a two hundred and fifth embodiment, the present invention provides amethod of treating cataplexy or excessive daytime sleepiness (EDS) in apatient with narcolepsy comprising: orally administering a dosage of acomposition comprising 4.5-9 g of gamma-hydroxybutyrate once per night,wherein the patient experiences a plasma GHB concentration maintainedthroughout the night, and gradual decline of the GHB concentration tolowest levels by 8 to 10 hours after dosing.

In a two hundred and sixth embodiment, the present invention provides amethod of treating cataplexy or excessive daytime sleepiness (EDS) in apatient with narcolepsy comprising: orally administering a dosage of acomposition comprising 4.5-9 g of gamma-hydroxybutyrate once per night,wherein the patient experiences a pharmacokinetic profile that supportsonce nightly dosing, and eliminates the need for the patient having towake up in the middle of the night to take a second dose.

In a two hundred and seventh embodiment, the present invention providesa method of treating cataplexy or excessive daytime sleepiness (EDS) ina patient with narcolepsy comprising: orally administering a dosage of acomposition comprising 4.5-9 g of gamma-hydroxybutyrate once per night,wherein the patient experiences a pharmacokinetic profile that supportsonce nightly dosing and a full 8 hours of consolidated nocturnal sleep.

In a two hundred and eighth embodiment, the present invention provides amethod of treating cataplexy or excessive daytime sleepiness (EDS) in achild or adolescent patient with narcolepsy comprising: orallyadministering a dosage of a composition comprising gamma-hydroxybutyrateonce per night, wherein the child or adolescent patient dosage is notcalculated based on weight of the patient.

Still further embodiments relate to methods of using the formulations ofthe present invention to treat narcolepsy and associated disorders andsymptoms, and to physical aspects of the formulations of the presentinvention. Additional principal embodiments and sub-embodiments theretowill be set forth in part in the description which follows, and in partwill be obvious from the description, or may be learned by practice ofthe invention. The embodiments and advantages of the invention will berealized and attained by means of the elements and combinationsparticularly pointed out in the appended claims. It is to be understoodthat both the foregoing general description and the following detaileddescription are exemplary and explanatory only and are not restrictiveof the invention, as claimed.

DESCRIPTION OF THE FIGURES

FIG. 1A depicts the qualitative and quantitative structure of theimmediate release (IR) microparticles of gamma-hydroxybutyrate ofExample 1. FIG. 1B depicts the qualitative and quantitative structure ofthe modified release (MR) microparticles of gamma-hydroxybutyrate ofExample 1.

FIG. 2 plots a time release dissolution profile of IR microparticles ofgamma-hydroxybutyrate of Example 1 (♦) and 1bis (▪) in a 0.1N HCldissolution medium.

FIG. 3 plots a time release dissolution profile of MR microparticles ofgamma-hydroxybutyrate of Example 1 in two sequential dissolution media(0.1 N HCl/phosphate buffer pH 6.8).

FIG. 4 plots a time release dissolution profile of MR microparticles (▴symbols) of Example 1 in two sequential dissolution media (0.1 NHCl/phosphate buffer pH 6.8), overlaid against dissolution profiledescribed in FIG. 3 of U.S. Pat. No. 8,193,211 (● symbols).

FIG. 5 plots a time release dissolution profile of the finishedformulation of Example 1 in deionized water.

FIG. 6 plots a time release dissolution profile of the finishedcomposition of Example 1 in deionized water (▴ symbols), overlaidagainst dissolution profile described in FIG. 2 of USP 2012/0076865 (●symbols).

FIG. 7 plots time release dissolution profiles in 0.1N HCl of fourseparate batches of finished compositions produced in accordance withExample 1 or Example 1bis.

FIG. 8 plots time release dissolution profiles in phosphate buffer pH6.8 of four separate batches of finished compositions produced inaccordance with Example 1 or Example 1bis.

FIG. 9 plots time release dissolution profiles in 0.1N HCl of MRmicroparticles of gamma-hydroxybutyrate produced in accordance withExample 1 at 75 rpm (▪ symbols) and 100 rpm (▴ symbols).

FIG. 10 plots time release dissolution profiles in 0.1N HCl of finishedcomposition produced in accordance with Example 1 performed with paddlerotation speed set at 75 rpm (▪ symbols) and 100 rpm (▴ symbols).

FIG. 11 plots the mean+SD (standard deviation) plasmagamma-hydroxybutyrate concentrations (microgram/mL) versus time for twodifferent modified release formulations of gamma-hydroxybutyrate testedin vivo according to the methods of Example 3. Time profiles are givenfor a 4.5 g dose of the finished composition of Example 1bisadministered once (● symbols) (N=26) and a 4.5 g dose of Xyrem®administered in two divided doses (- symbols) (N=15).

FIG. 12 plots the mean+SD (standard deviation) plasmagamma-hydroxybutyrate concentrations (microgram/mL) versus time after aSingle Oral Administration of 4.5 g (● symbols) and 6 g (▴ symbols) offinished composition of Example 1bis in the same 7 subjects tested invivo according to the methods of Example 3.

FIG. 13 plots the mean+SD (standard deviation) plasmagamma-hydroxybutyrate concentrations (microgram/mL) versus time of threeseparate doses of finished composition prepared according to Example1bis tested in vivo according to the methods of Example 3. Mean timeprofiles are given for a single oral administration of 4.5 g (N=26) (□),6.0 g (N=19) (▴) or 7.5 g (▪) doses (N=11).

FIG. 14 plots the mean plasma gamma-hydroxybutyrate Concentrations(microgram/mL) of a Single dose of 7.5 g (▪) of finished compositionprepared according to Example 1bis compared to 2×4.5 g Xyrem® post-fed(Source NDA 21-196 review).

FIG. 15A depicts the qualitative and quantitative structure of theimmediate release (IR) microparticles of gamma-hydroxybutyrate ofExample 4. FIG. 15B depicts the qualitative and quantitative structureof the modified release (MR) microparticles of gamma-hydroxybutyrate ofExample 4.

FIG. 16 plots a time release dissolution profile of MR microparticles ofgamma-hydroxybutyrate of Example 4 in two sequential dissolution media(0.1 N HCl and phosphate buffer pH 6.8).

FIG. 17 plots a time release dissolution profile of MR microparticles (▴symbols) of Example 4 in two sequential dissolution media (0.1 N HCl andphosphate buffer pH 6.8), overlaid against dissolution profile describedin FIG. 3 of U.S. Pat. No. 8,193,211 (● symbols).

FIG. 18 plots a time release dissolution profile of the finishedcomposition of Example 4 in deionized water.

FIG. 19 plots a time release dissolution profile of the finishedcomposition of Example 4 in deionized water (● symbols), overlaidagainst dissolution profile described in FIG. 2 of USP 2012/0076865 (▴symbols).

FIG. 20 plots time release dissolution profiles in 0.1N HCl of threeseparate batches of finished compositions produced in accordance withExample 4 or 4bis.

FIG. 21 plots a time release dissolution profile in phosphate buffer pH6.8 of a finished composition produced in accordance with Example 4.

FIG. 22 plots mean plasma gamma-hydroxybutyrate concentration(microgram/mL) time profiles after a Single Dose of 4.5 g (▪) offinished composition of Example 4bis, N=15 compared to 2×2.25 g Xyrem®post fed, N=15.

FIG. 23A depicts the qualitative and quantitative structure of theimmediate release (IR) microparticles of gamma-hydroxybutyrate ofExample 7. FIG. 23B depicts the qualitative and quantitative structureof the modified release (MR) microparticles of gamma-hydroxybutyrate ofExample 7.

FIG. 24 plots a time release dissolution profile of MR microparticles ofgamma-hydroxybutyrate of Example 7 (▴ symbols) in two sequentialdissolution media (0.1 N HCl and phosphate buffer pH 6.8), overlaidagainst dissolution profile described in FIG. 3 of U.S. Pat. No.8,193,211 (● symbols).

FIG. 25 plots the Min (▪) and Max (▴) values of a preferred dissolutionprofile in 0.1N HCl of finished composition according to the invention.

FIG. 26 plots the Min (▪) and Max (▴) values of a preferred dissolutionprofile in phosphate buffer pH 6.8 of finished composition according tothe invention.

FIG. 27 plots the Min (▪) and Max (▴) values of another preferreddissolution profile in phosphate buffer pH 6.8 of finished compositionaccording to the invention.

FIG. 28 plots the Min (▪) and Max (▴) values of another preferreddissolution profile in 0.1N HCl of finished composition according to theinvention.

FIG. 29 depicts a dissolution profile determined in 0.1N HCl using a USPapparatus 2 for the formulation of Example 9.1 5 minutes and 15 minutesafter reconstitution in water.

FIG. 30 depicts a dissolution profile determined in 0.1N HCl using a USPapparatus 2 for the formulation of Example 9.2 5 minutes and 15 minutesafter reconstitution in water.

FIG. 31 depicts a dissolution profile determined in 0.1N HCl using a USPapparatus 2 for the formulation of Example 9.3 5 minutes and 15 minutesafter reconstitution in water.

FIG. 32 depicts the dissolution profile determined in 0.1N HCl using aUSP apparatus 2 of a 9 g dose of the formulation of Example 10 with andwithout rinsing.

FIG. 33 depicts the dissolution profile of the MR portion of theformulation of Example 11a in 900 ml of 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2.

FIG. 34 depicts the dissolution profile of the formulation of Example11a in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 35 depicts the dissolution profile of the formulation of Example11a in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 36 depicts the dissolution profile of the MR portion of theformulation of Example 11b in 900 ml of 0.1N HCl using a USP apparatus2.

FIG. 37 depicts the dissolution profile of the formulation of Example11b in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 38 depicts the dissolution profile of the formulation of Example11b in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 39 depicts the dissolution profile of the formulation of Example11c in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 40 depicts the dissolution profile of the formulation of Example11c in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 41 depicts the dissolution profile of the MR portion of theformulation of Example 12a in 900 ml of 0.1N HCl using a USP apparatus2.

FIG. 42 depicts the dissolution profile of the formulation of Example12a using a USP apparatus 2 in 0.1N HCl.

FIG. 43 depicts the dissolution profile of the formulation of Example12b in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 44 depicts the dissolution profile of the formulation of Example12b in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 45 depicts the dissolution profile of the MR portion of theformulation of Example 13 in 900 ml of 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2.

FIG. 46 depicts the dissolution profile of the formulation of Example 13in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 47 depicts the dissolution profile of the formulation of Example 13in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 48 depicts the dissolution profile of the MR portion of theformulation of Example 14 in 900 ml of 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2.

FIG. 49 depicts the dissolution profile of the formulation of Example 14in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 50 depicts the dissolution profile of the formulation of Example 14in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 51 depicts the dissolution profile of the MR portion of theformulation of Example 15a (coating weight 35%) in 900 ml of 0.1N HClusing a USP apparatus 2.

FIG. 52 depicts the dissolution profile of the MR portion of theformulation of Example 15a (coating weight 50%) in 900 ml of 0.1N HClusing a USP apparatus 2.

FIG. 53 depicts the dissolution profile of the formulation of Example15a in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 54 depicts the dissolution profile of the MR portion of theformulation of Example 15b in 900 ml of 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2.

FIG. 55 depicts the dissolution profile of the formulation of Example15b in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 56 depicts the dissolution profile of the formulation of Example15b in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 57 depicts the dissolution profile of the MR portion of theformulation of Example 15c in 900 ml of 0.1N HCl using a USP apparatus2.

FIG. 58 depicts the dissolution profile of the formulation of Example15c in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 59 depicts the dissolution profile of the formulation of Example15c in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 60 depicts the dissolution profile of the MR portion of theformulation of Example 15d in 900 ml of 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2.

FIG. 61 depicts the dissolution profile of the formulation of Example15d in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 62 depicts the dissolution profile of the formulation of Example15d in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 63 depicts the dissolution profile of the MR portion of theformulation of Example 16a in 900 ml of 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2.

FIG. 64 depicts the dissolution profile of the formulation of Example16a in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 65 depicts the dissolution profile of the formulation of Example16a in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 66 depicts the dissolution profile of the MR portion of theformulation of Example 16b in 900 ml of 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2.

FIG. 67 depicts the dissolution profile of the formulation of Example16b in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 68 depicts the dissolution profile of the formulation of Example16b in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 69 depicts the dissolution profile of the MR portion of theformulation of Example 16c in 900 ml of 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2.

FIG. 70 depicts the dissolution profile of the formulation of Example16c in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 71 depicts the dissolution profile of the formulation of Example16c in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 72 depicts the dissolution profile of the MR portion of theformulation of Example 16d in 900 ml of 0.1N HCl using a USP apparatus2.

FIG. 73 depicts the dissolution profile of the MR portion of theformulation of Example 17a in 900 ml of 0.1N HCl using a USP apparatus2.

FIG. 74 depicts the dissolution profile of the formulation of Example17a in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 75 depicts the dissolution profile of the formulation of Example17a in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 76 depicts the dissolution profile of the MR portion of theformulation of Example 17b in 900 ml of 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2.

FIG. 77 depicts the dissolution profile of the formulation of Example17b in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 78 depicts the dissolution profile of the formulation of Example17b in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 79 depicts the dissolution profile of the MR portion of theformulation of Example 17c in 900 ml of 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2.

FIG. 80 depicts the dissolution profile of the formulation of Example17c in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 81 depicts the dissolution profile of the formulation of Example17c in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 82 depicts a preferred dissolution profile of sodium oxybate MRmicroparticles in 900 ml 0.1N HCl using a USP apparatus 2 at 75 rpm.

FIG. 83 depicts a preferred dissolution profile of sodium oxybate MRmicroparticles in 900 ml pH 6.8 phosphate buffer (0.05M monobasicpotassium phosphate solution—pH adjusted to 6.8 with 5N NaOH) using aUSP apparatus 2 at 75 rpm.

FIG. 84 depicts a preferred dissolution profile of a sodium oxybatefinished formulation comprising IR and MR microparticles in 900 ml 0.1NHCl using a USP apparatus 2 at 75 rpm.

FIG. 85 depicts a preferred dissolution profile of a sodium oxybatefinished formulation comprising IR and MR microparticles in 900 ml pH6.8 phosphate buffer (0.05M monobasic potassium phosphate solution—pHadjusted to 6.8 with 5N NaOH) using a USP apparatus 2 at 75 rpm.

FIG. 86 is a dissolution profile in 0.1N HCl of two separate batches ofthe sodium oxybate MR microparticles present in the finished compositionof Example 18.

FIG. 87 is a dissolution profile in phosphate buffer pH 6.8 of twoseparate batches of the sodium oxybate MR microparticles present in thefinished composition of Example 18.

FIG. 88 is a dissolution profile in 0.1N HCl of two unit doses of 3 g (▴symbols) and 4.5 g (● symbols) of the finished composition of Example18.

FIG. 89 is a dissolution profile in phosphate buffer pH 6.8 of two unitdoses of 3 g (▴ symbols) and 4.5 g (● symbols) of the finishedcomposition of Example 18.

FIG. 90 plots mean plasma gamma-hydroxybutyrate concentrations(microgram/mL)+SD−time profiles after a single oral administration of4.5 g (● symbols), 7.5 g (▪ symbols) and 9 g (▴ symbols) of the finishedcomposition of Example 18.

FIG. 91 is a top isometric view of a closed 30-day supply carton in oneexample.

FIG. 92 is a front elevational view of FIG. 91 ;

FIG. 93 is a rear elevational view of FIG. 91 ;

FIG. 94 is a right side elevational view of FIG. 91 ;

FIG. 95 is a left side elevational view of FIG. 91 ;

FIG. 96 is a top plan view of FIG. 91 .

FIG. 97 is a bottom plan view of FIG. 91 .

FIG. 98 is a top isometric view of a mixing cup receptacle insert in oneexample.

FIG. 99 is a front elevational view of FIG. 98 ;

FIG. 100 is a rear elevational view of FIG. 98 ;

FIG. 101 is a right side elevational view of FIG. 98 ;

FIG. 102 is a left side elevational view of FIG. 98 ;

FIG. 103 is a top plan view of FIG. 98 .

FIG. 104 is a bottom plan view of FIG. 98 .

FIG. 105 is a top isometric view of a mixing cup in one example.

FIG. 106 is a front elevational view of FIG. 105 ;

FIG. 107 is a rear elevational view of FIG. 105 ;

FIG. 108 is a right side elevational view of FIG. 105 ;

FIG. 109 is a left side elevational view of FIG. 105 ;

FIG. 110 is a top plan view of FIG. 105 .

FIG. 111 is a bottom plan view of FIG. 105 .

FIG. 112 is a top isometric view of a once-nightly dose packet containerin one example.

FIG. 113 is a front elevational view of FIG. 112 ;

FIG. 114 is a rear elevational view of FIG. 112 ;

FIG. 115 is a right side elevational view of FIG. 112 ;

FIG. 116 is a left side elevational view of FIG. 112 ;

FIG. 117 is a top plan view of FIG. 112 .

FIG. 118 is a bottom plan view of FIG. 112 .

FIG. 119 is a top isometric view of a once-nightly dose packet in oneexample.

FIG. 120 is a front elevational view of FIG. 119 ;

FIG. 121 is a rear elevational view of FIG. 119 ;

FIG. 122 is a right side elevational view of FIG. 119 ;

FIG. 123 is a left side elevational view of FIG. 119 ;

FIG. 124 is a top plan view of FIG. 119 .

FIG. 125 is a bottom plan view of FIG. 119 .

FIG. 126 is an exploded top isometric view of an open 30-day supplycarton with 30 once-nightly dose packets, a mixing cup, and respectivecontainers and receptacle, in one example.

FIG. 127 is a top isometric view of an open 30-day supply carton with 30once-nightly dose packets, a mixing cup, and respective containers andreceptacle, in one example.

FIG. 128 is a top plan view of FIG. 127 .

FIG. 129 is a top isometric view of a closed 7-day supply carton in oneexample.

FIG. 130 is an exploded top isometric view of an open 7-day supplycarton with 7 once-nightly dose packets, a mixing cup, and respectivecontainer and receptacle, in one example.

FIG. 131 is a top isometric view of an open 7-day supply carton with 7once-nightly dose packets, a mixing cup, and respective container andreceptacle, in one example.

FIG. 132 is a top plan view of FIG. 131 .

FIG. 133A, FIG. 133B, FIG. 133C, and FIG. 133D are example instructionsfor use of the composition in a once-nightly dosing packet andsuspension in water using the mixing cup.

FIG. 134 shows mean plasma concentrations of γ-hydroxybutyrate (GHB)over time after twice-nightly sodium oxybate (SO) or 3 formulations ofFT218 in the pilot study. Error bars indicate SEs.

FIG. 135 shows mean plasma concentrations of γ-hydroxybutyrate (GHB)over time after 3 dose levels of FT218 in the dose-proportionalitystudy. Error bars indicate SEs.

FIG. 136 shows mean plasma concentrations of γ-hydroxybutyrate (GHB)over time after FT218 or twice-nightly sodium oxybate (SO) in therelative bioequivalence study. Error bars indicate SEs.

FIG. 137 mean plasma concentrations of γ-hydroxybutyrate (GHB) over timeafter FT218 administration in fasted or fed participants in thefood-effect study. Error bars indicate SEs.

FIG. 138A shows dissolution profiles for Trials 1-3 for 4.5 g FT218 withtwo different cups.

FIG. 138B shows dissolution profiles for Trials 1-3 for 9 g FT218 withtwo different cups.

FIG. 139A shows a chromatogram for Trial 1 of the mixing cup assessmentand FIG. 139B shows a chromatogram for Trial 2 of the mixing cupassessment.

DETAILED DESCRIPTION OF THE INVENTION

The present invention may be understood more readily by reference to thefollowing detailed description of preferred embodiments of the inventionand the Examples included therein.

Definitions and Use of Terms

Wherever an analysis or test is required to understand a given propertyor characteristic recited herein, it will be understood that theanalysis or test is performed in accordance with applicable guidances,draft guidances, regulations and monographs of the United States Foodand Drug Administration (“FDA”) and United States Pharmacopoeia (“USP”)applicable to drug products in the United States in force as of Nov. 1,2015 unless otherwise specified. Clinical endpoints can be judged withreference to standards adopted by the American Academy of SleepMedicine, including standards published at C Iber, S Ancoli-Israel, AChesson, SF Quan. The AASM Manual for the Scoring of Sleep andAssociated Events. Westchester, IL: American Academy of Sleep Medicine;2007.

When a pharmacokinetic comparison is made between a formulationdescribed or claimed herein and a reference product, it will beunderstood that the comparison is preferably performed in a suitabledesigned cross-over trial, although it will also be understood that across-over trial is not required unless specifically stated. It willalso be understood that the comparison may be made either directly orindirectly. For example, even if a formulation has not been testeddirectly against a reference formulation, it may still satisfy acomparison to the reference formulation if it has been tested against adifferent formulation, and the comparison with the reference formulationmay be deduced therefrom.

As used in this specification and in the claims which follow, thesingular forms “a,” “an” and “the” include plural referents unless thecontext dictates otherwise. Thus, for example, reference to “aningredient” includes mixtures of ingredients, reference to “an activepharmaceutical agent” includes more than one active pharmaceuticalagent, and the like.

“Bioavailability” means the rate and extent to which the activeingredient or active moiety is absorbed from a drug product and becomesavailable at the site of action.

“Relative bioavailability” or “Rel BA” or “RBA” means the percentage ofmean AUCinf of the tested product relative to the mean AUCinf of thereference product. Unless otherwise specified, relative bioavailabilityrefers to the percentage of the mean AUCinf observed for a full dose ofthe test product relative to the mean AUCinf observed for two ½-doses ofan immediate release liquid solution administered four hours apart.

“Bioequivalence” means the absence of a significant difference in therate and extent to which the active ingredient or active moiety inpharmaceutical equivalents or pharmaceutical alternatives becomeavailable at the site of drug action when administered at the same molardose under similar conditions in an appropriately designed study.

When ranges are given by specifying the lower end of a range separatelyfrom the upper end of the range, it will be understood that the rangemay be defined by selectively combining any one of the lower endvariables with any one of the upper end variables that is mathematicallyand physically possible. Thus, for example, if a formulation may containfrom 1 to 10 weight parts of a particular ingredient, or 2 to 8 parts ofa particular ingredient, it will be understood that the formulation mayalso contain from 2 to 10 parts of the ingredient. In like manner, if aformulation may contain greater than 1 or 2 weight parts of aningredient and up to 10 or 9 weight parts of the ingredient, it will beunderstood that the formulation may contain 1-10 weight parts of theingredient, 2-9 weight parts of the ingredient, etc. unless otherwisespecified, the boundaries of the range (lower and upper ends of therange) are included in the claimed range.

In like manner, when various sub-embodiments of a senior (i.e.principal) embodiment are described herein, it will be understood thatthe sub-embodiments for the senior embodiment may be combined to defineanother sub-embodiment. Thus, for example, when a principal embodimentincludes sub-embodiments 1, 2 and 3, it will be understood that theprincipal embodiment may be further limited by any one ofsub-embodiments 1, 2 and 3, or any combination of sub-embodiments 1, 2and 3 that is mathematically and physically possible. In like manner, itwill be understood that the principal embodiments described herein maybe combined in any manner that is mathematically and physicallypossible, and that the invention extends to such combinations.

When used herein the term “about” or “substantially” or “approximately”will compensate for variability allowed for in the pharmaceuticalindustry and inherent in pharmaceutical products, such as differences inproduct strength due to manufacturing variation and time-induced productdegradation. The term allows for any variation which in the practice ofpharmaceuticals would allow the product being evaluated to be consideredbioequivalent to the recited strength, as described in FDA's March 2003Guidance for Industry on BIOAVAILABILITY AND BIOEQUIVALENCE STUDIES FORORALLY ADMINISTERED DRUG PRODUCTS—GENERAL CONSIDERATIONS.

When used herein the term “gamma-hydroxybutyrate” or GHB, unlessotherwise specified, refers to the free base of gamma hydroxy-butyrate,a pharmaceutically acceptable salt of gamma-hydroxybutyric acid, andcombinations thereof, their hydrates, solvates, complexes or tautomersforms. Gamma-hydroxybutyric acid salts may be selected from the sodiumsalt of gamma-hydroxybutyric acid or sodium oxybate, the potassium saltof gamma-hydroxybutyric acid, the magnesium salt of gamma-hydroxybutyricacid, the calcium salt of gamma-hydroxybutyric acid, the lithium salt ofgamma-hydroxybutyric, the tetra ammonium salt of gamma-hydroxybutyricacid or any other pharmaceutically acceptable salt forms ofgamma-hydroxybutyric acid and mixtures thereof.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use. Theterm “formulation” or “composition” refers to the quantitative andqualitative characteristics of a drug product or dosage form prepared inaccordance with the current invention.

As used herein the doses and strengths of gamma-hydroxybutyrate areexpressed in equivalent-gram (g) weights of sodium oxybate unless statedexpressly to the contrary. Thus, when considering a dose ofgamma-hydroxybutyrate other than the sodium salt ofgamma-hydroxybutyrate, one must convert the recited dose or strengthfrom sodium oxybate to the gamma-hydroxybutyrate under evaluation. Thus,if an embodiment is said to provide a 4.5 g dose ofgamma-hydroxybutyrate, because the form of gamma-hydroxybutyrate is notspecified, it will be understood that the dose encompasses a 4.5 g doseof sodium oxybate, a 5.1 g dose of potassium gamma-hydroxybutyrate(assuming a 126.09 g/mol MW for sodium oxybate and a 142.20 g/mol MW forpotassium gamma-hydroxybutyrate), and a 3.7 g dose of the free base(assuming a 126.09 g/mol MW for sodium oxybate and a 104.1 g/mol MW forthe free base of gamma-hydroxybutyrate), or by the weight of any mixtureof salts of gamma-hydroxybutyric acid that provides the same amount ofGHB as 4.5 g of sodium oxybate.

As used herein “microparticle” means any discreet particle of solidmaterial. The particle may be made of a single material or have acomplex structure with core and shells and be made of several materials.The terms “microparticle”, “particle”, “microspheres” or “pellet” areinterchangeable and have the same meaning. Unless otherwise specified,the microparticle has no particular particle size or diameter and is notlimited to particles with volume mean diameter D(4,3) below 1 mm.

As used herein, the “volume mean diameter D(4,3)” is calculatedaccording to the following formula:

D(4,3)=Σ(d ⁴ _(i) ·n _(i))/Σ(d ³ _(i) ·n _(i))

wherein the diameter d of a given particle is the diameter of a hardsphere having the same volume as the volume of that particle.

As used herein, the terms “finished composition”, “finished formulation”or “formulation” are interchangeable and designate the modified releaseformulation of gamma-hydroxybutyrate preferably comprising modifiedrelease microparticles of gamma-hydroxybutyrate, immediate releasemicroparticles of gamma-hydroxybutyrate, and any other excipients.

As used herein and in the claims that follow, an “immediate release (IR)portion” of a formulation includes physically discreet portions of aformulation, mechanistically discreet portions of a formulation, andpharmacokinetically discreet portions of a formulation that lend to orsupport a defined IR pharmacokinetic characteristic. Thus, for example,any formulation that releases active ingredient at the rate and extentrequired of the immediate release portion of the formulations of thepresent invention includes an “immediate release portion,” even if theimmediate release portion is physically integrated in what mightotherwise be considered an extended release formulation. Thus, the IRportion may be structurally discreet or structurally indiscreet from(i.e. integrated with) the MR portion. In a preferred embodiment, the IRportion and MR portion are provided as particles, and in an even morepreferred sub-embodiment the IR portion and MR portion are provided asparticles discreet from each other.

As used here in, “immediate release formulation” or “immediate releaseportion” refers to a composition that releases at least 80% of itsgamma-hydroxybutyrate in 1 hour when tested in a dissolution apparatus 2according to USP 38 <711> in a 0.1N HCl dissolution medium at atemperature of 37° C. and a paddle speed of 75 rpm.

In like manner, a “modified-release (MR) portion” includes that portionof a formulation or dosage form that lends to or supports a particularMR pharmacokinetic characteristic, regardless of the physicalformulation in which the MR portion is integrated. The modified releasedrug delivery systems are designed to deliver drugs at a specific timeor over a period of time after administration, or at a specific locationin the body. The USP defines a modified release system as one in whichthe time course or location of drug release or both, are chosen toaccomplish objectives of therapeutic effectiveness or convenience notfulfilled by conventional IR dosage forms. More specifically, MR solidoral dosage forms include extended release (ER) and delayed-release (DR)products. A DR product is one that releases a drug all at once at a timeother than promptly after administration. Typically, coatings (e.g.,enteric coatings) are used to delay the release of the drug substanceuntil the dosage form has passed through the acidic medium of thestomach. An ER product is formulated to make the drug available over anextended period after ingestion, thus allowing a reduction in dosingfrequency compared to a drug presented as a conventional dosage form,e.g. a solution or an immediate release dosage form. For oralapplications, the term “extended-release” is usually interchangeablewith “sustained-release”, “prolonged-release” or “controlled-release”.

Traditionally, extended-release systems provided constant drug releaseto maintain a steady concentration of drug. For some drugs, however,zero-order delivery may not be optimal and more complex andsophisticated systems have been developed to provide multiphasedelivery. One may distinguish among four categories of oral MR deliverysystems: (1) delayed-release using enteric coatings, (2) site-specificor timed release (e.g. for colonic delivery), (3) extended-release(e.g., zero-order, first-order, biphasic release, etc.), and (4),programmed release (e.g., pulsatile, delayed extended release, etc.) SeeModified Oral Drug Delivery Systems at page 34 in Gibaldi's DRUGDELIVERY SYSTEMS IN PHARMACEUTICAL CARE, AMERICAN SOCIETY OFHEALTH-SYSTEM PHARMACISTS, 2007 and Rational Design of OralModified-release Drug Delivery Systems at page 469 in DEVELOPING SOLIDORAL DOSAGE FORMS: PHARMACEUTICAL THEORY AND PRACTICE, Academic Press,Elsevier, 2009. As used herein, “modified release formulation” or“modified release portion” in one embodiment refers to a compositionthat releases its gamma-hydroxybutyrate according a multiphase deliverythat is comprised in the fourth class of MR products, e.g. delayedextended release. As such it differs from the delayed release productsthat are classified in the first class of MR products.

As used herein the terms “coating”, “coating layer,” “coating film,”“film coating” and like terms are interchangeable and have the samemeaning. The terms refer to the coating applied to a particle comprisingthe gamma-hydroxybutyrate that controls the modified release of thegamma-hydroxybutyrate.

In all pharmacokinetic testing described herein, unless otherwisestated, the dosage form, or the initial dosage form if the dosingregimen calls for more than one administration, is administeredapproximately two hours after consumption of a standardized dinnerconsisting of 25.5% fat, 19.6% protein, and 54.9% carbohydrates.

A “similar PK profile” or “comparable bioavailability” means that themean AUCinf of a test product is from 80% to 125% of the mean AUCinf ofa reference product in a suitably designed cross-over trial, and thatthe mean plasma concentration at 8 hours (C8 h) of the test product isfrom 50% to 130% of the mean plasma concentration at 8 hours (C8 h) ofthe reference product.

Type 1 Narcolepsy (NT1) refers to narcolepsy characterized by excessivedaytime sleepiness (“EDS”) and cataplexy. Type 2 Narcolepsy (NT2) refersto narcolepsy characterized by excessive daytime sleepiness withoutcataplexy. A diagnosis of narcolepsy (with or without cataplexy) may beconfirmed by one or a combination of (i) an overnight polysomnogram(PSG) and a Multiple Sleep Latency Test (MSLT) performed within the last2 years, (ii) a full documentary evidence confirming diagnosis from thePSG and MSLT from a sleep laboratory must be made available, (iii)current symptoms of narcolepsy including: current complaint of EDS forthe last 3 months (ESS greater than 10), (iv) mean MWT less than 8minutes, (v) mean number of cataplexy events of 8 per week on baselineSleep/Cataplexy Diary, and/or (vi) presence of cataplexy for the last 3months and 28 events per week during screening period.

Unless otherwise specified herein, percentages, ratios and numericvalues recited herein are based on weight; averages and means arearithmetic means; all pharmacokinetic measurements based on themeasurement of bodily fluids are based on plasma concentrations.

It will be understood, when defining a composition by itspharmacokinetic or dissolution properties herein, that the formulationmay in the alternative be defined as “means for” achieving the recitedpharmacokinetic or dissolution properties. Thus, a formulation in whichthe modified release portion releases less than 20% of itsgamma-hydroxybutyrate at one hour may instead be defined as aformulation comprising “means for” or “modified release means for”releasing less than 20% of its gamma-hydroxybutyrate at one hour. Itwill be further understood that the preferred structures for achievingthe recited pharmacokinetic or dissolution properties are the structuresdescribed in the examples hereof that accomplish the recitedpharmacokinetic or dissolution properties.

DISCUSSION OF PRINCIPAL EMBODIMENTS

The invention may be described in terms of principal embodiments, whichin turn may be recombined to make other principal embodiments, andlimited by sub-embodiments to make other principal embodiments.

A first embodiment provides a method of treating cataplexy or excessivedaytime sleepiness (EDS) in a patient with narcolepsy, the methodcomprising: orally administering a dosage of a composition comprisingsodium oxybate once per night, wherein the patient experiences feweradverse reactions as compared to a second patient administeredtwice-nightly sodium oxybate treatment.

A second embodiment provides a method comprising: orally administering adosage of a composition comprising sodium oxybate once per night,wherein the patient experiences no adverse reactions.

A third embodiment provides a method comprising: orally administering adosage of a composition comprising sodium oxybate once per night,wherein the patient experiences less or no obtundation as compared tothe twice-nightly sodium oxybate treatment.

A fourth embodiment provides a method comprising: orally administering adosage of a composition comprising sodium oxybate once per night,wherein the patient experiences less or no clinically significantrespiratory depression as compared to the twice-nightly sodium oxybatetreatment.

A fifth embodiment provides a method comprising: orally administering adosage of a composition comprising sodium oxybate once per night,wherein the patient does not have profound CNS depression or severedifficulty breathing at doses of 4.5 g to 9 g sodium oxybate per night.

A sixth embodiment provides a method comprising: orally administering adosage of a composition comprising sodium oxybate once per night,wherein the patient does not have a clinically significant worsening ofrespiratory function as measured by apnea/hypopnea index and pulseoximetry at doses of 4.5 g to 9 g sodium oxybate per night.

A seventh embodiment provides a method comprising: orally administeringa dosage of a composition comprising sodium oxybate once per night,wherein the patient has statistically significant improvement on theMaintenance of Wakefulness Test at dosages of 6 g, 7.5 g, and 9 g ascompared to placebo. In some aspects, the patient has a latency to sleeponset about 5 minutes or more than placebo.

An eighth embodiment provides a method comprising: orally administeringa dosage of a composition comprising sodium oxybate once per night,wherein the patient has statistically significant improvement on theClinical Global Impression-Improvement at dosages of 6 g, 7.5 g, and 9 gas compared to placebo. In some aspects, the patient is 5 times or morelikely to respond as much or very much improved as compared to placebo.

A ninth embodiment provides a method comprising: orally administering adosage of a composition comprising sodium oxybate once per night,wherein the patient has statistically significant improvement in meanweekly cataplexy attacks at dosages of 6 g, 7.5 g, and 9 g as comparedto placebo. In some aspects, the patient has about 4 or fewer meancataplexy attacks per week as compared to placebo.

A tenth embodiment provides a method comprising: orally administering adosage of a composition comprising sodium oxybate once per night,wherein a peak plasma concentration (C_(max)) following administrationof one dose is lower than a twice-nightly sodium oxybate treatment. Insome aspects, the C_(max) following administration of one 6 g dose isabout 65.8 mcg/mL. In other aspects, there is a steady decrease inconcentration following a time to peak plasma concentration (T_(max))approximately two hours after dosing. In additional aspects, the T_(max)is about 1.51 hours.

An eleventh embodiment provides a method comprising: orallyadministering a dosage of a composition comprising sodium oxybate onceper night, wherein the dosage of the composition initially administeredcomprises 4.5 g sodium oxybate. In some aspects, the method furthercomprises increasing the dosage by 1.5 g per night at weekly intervalsto an effective dosage range of 6 g to 9 g per night.

A twelfth embodiment provides a method comprising: orally administeringa dosage of a composition comprising sodium oxybate once per night,wherein the composition is a powder for oral suspension. In someaspects, the composition comprises immediate-release andcontrolled-release granules comprising sodium oxybate and may furthercomprise microcrystalline cellulose spheres, povidone K30, hydrogenatedvegetable oil, methacrylic acid copolymer, malic acid, xanthan gum,hydroxyethyl cellulose, carrageenan, and/or magnesium stearate.

A thirteenth embodiment provides a method comprising: providing thecomposition in a nightly dose packet of 4.5 g, 6 g, 7.5, g, or 9 gsodium oxybate, wherein the composition is a powder for oral suspension;and orally administering a dosage of a composition comprising sodiumoxybate once per night.

A fourteenth embodiment provides a method comprising: providing thecomposition in a nightly dose packet of 4.5 g, 6 g, 7.5, g, or 9 gsodium oxybate, wherein the composition is a powder for oral suspension;preparing the dosage by suspending the composition from the dose packetin water; and orally administering a dosage of a composition comprisingsodium oxybate once per night. In some aspects, the dosage is suspendedin approximately 50 mL of water.

A fifteenth embodiment provides a method comprising: orallyadministering a dosage of a composition comprising sodium oxybate onceper night, wherein the dosage is administered without regard for meals.

A sixteenth embodiment provides a method comprising: orallyadministering a dosage of a composition comprising sodium oxybate onceper night, wherein the patient is in bed prior to orally administeringthe dosage. In some aspects, the patient lays down immediately afteradministering the dosage.

A seventeenth embodiment provides a method comprising: orallyadministering a dosage of a composition comprising sodium oxybate onceper night, wherein the patient falls asleep within 5 minutes to 15minutes after administering the dosage.

An eighteenth embodiment provides a method comprising: orallyadministering a dosage of a composition comprising sodium oxybate onceper night and administering single dose of divalproex sodium ER. In someaspects, the dose of divalproex sodium ER is about 1250 mg.

A nineteenth embodiment provides a method comprising: orallyadministering a dosage of a composition comprising sodium oxybate onceper night, wherein the patient is an adult.

A twentieth embodiment provides a method of treating cataplexy orexcessive daytime sleepiness (EDS) in a patient with narcolepsy, themethod comprising: orally administering a dosage of a compositioncomprising sodium oxybate once per night, wherein the patientexperiences less obtundation as compared to a twice-nightly sodiumoxybate treatment.

A twenty first embodiment provides a method comprising: orallyadministering a dosage of a composition comprising sodium oxybate onceper night, wherein the patient experiences no obtundation.

A twenty second embodiment provides a method comprising: orallyadministering a dosage of a composition comprising sodium oxybate onceper night, wherein the patient experiences less or no clinicallysignificant respiratory depression as compared to the twice-nightlysodium oxybate treatment.

A twenty third embodiment provides a method comprising: orallyadministering a dosage of a composition comprising sodium oxybate onceper night, wherein the patient does not have profound CNS depression orsevere difficulty breathing at doses of 4.5 g to 9 g sodium oxybate pernight.

A twenty fourth embodiment provides a method comprising: orallyadministering a dosage of a composition comprising sodium oxybate onceper night, wherein the patient does not have a clinically significantworsening of respiratory function as measured by apnea/hypopnea indexand pulse oximetry at doses of 4.5 g to 9 g sodium oxybate per night.

A twenty fifth embodiment provides a method comprising: orallyadministering a dosage of a composition comprising sodium oxybate onceper night, wherein the patient has statistically significant improvementon the Maintenance of Wakefulness Test at dosages of 6 g, 7.5 g, and 9 gas compared to placebo. In some aspects, the patient has a latency tosleep onset about 5 minutes or more than placebo.

A twenty sixth embodiment provides a method comprising: orallyadministering a dosage of a composition comprising sodium oxybate onceper night, wherein the patient has statistically significant improvementon the Clinical Global Impression-Improvement at dosages of 6 g, 7.5 g,and 9 g as compared to placebo. In some aspects, the patient is 5 timesor more likely to respond as much or very much improved as compared toplacebo.

A twenty seventh embodiment provides a method comprising: orallyadministering a dosage of a composition comprising sodium oxybate onceper night, wherein the patient has statistically significant improvementin mean weekly cataplexy attacks at dosages of 6 g, 7.5 g, and 9 g ascompared to placebo. In some aspects, the patient has about 4 or fewermean cataplexy attacks per week as compared to placebo.

A twenty ninth embodiment provides a method of treating cataplexy orexcessive daytime sleepiness (EDS) in a patient with narcolepsy, themethod comprising: orally administering a dosage of a compositioncomprising sodium oxybate once per night, wherein the patientexperiences less respiratory depression as compared to a twice-nightlysodium oxybate treatment.

A thirtieth embodiment provides a method comprising: orallyadministering a dosage of a composition comprising sodium oxybate onceper night, wherein the patient experiences no clinically significantrespiratory depression.

A thirty first embodiment provides a method comprising: orallyadministering a dosage of a composition comprising sodium oxybate onceper night, wherein the patient experiences less or no obtundation ascompared to the twice-nightly sodium oxybate treatment.

A thirty second embodiment provides a method comprising: orallyadministering a dosage of a composition comprising sodium oxybate onceper night, wherein the patient does not have profound CNS depression orsevere difficulty breathing at doses of 4.5 g to 9 g sodium oxybate pernight.

A thirty third embodiment provides a method comprising: orallyadministering a dosage of a composition comprising sodium oxybate onceper night, wherein the patient does not have a clinically significantworsening of respiratory function as measured by apnea/hypopnea indexand pulse oximetry at doses of 4.5 g to 9 g sodium oxybate per night.

A thirty fourth embodiment provides a method comprising: orallyadministering a dosage of a composition comprising sodium oxybate onceper night, wherein the patient has statistically significant improvementon the Maintenance of Wakefulness Test at dosages of 6 g, 7.5 g, and 9 gas compared to placebo. In some aspects, the patient has a latency tosleep onset about 5 minutes or more than placebo.

A thirty fifth embodiment provides a method comprising: orallyadministering a dosage of a composition comprising sodium oxybate onceper night, wherein the patient has statistically significant improvementon the Clinical Global Impression-Improvement at dosages of 6 g, 7.5 g,and 9 g as compared to placebo. In some aspects, the patient is 5 timesor more likely to respond as much or very much improved as compared toplacebo.

A thirty sixth embodiment provides a method comprising: orallyadministering a dosage of a composition comprising sodium oxybate onceper night, wherein the patient has statistically significant improvementin mean weekly cataplexy attacks at dosages of 6 g, 7.5 g, and 9 g ascompared to placebo. In some aspects, the patient has about 4 or fewermean cataplexy attacks per week as compared to placebo.

A thirty seventh embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the modified release formulation is suitable foradministration only once nightly, without obtundation and clinicallysignificant respiratory depression occurring in adult patients treatedwith twice-nightly sodium oxybate.

A thirty eighth embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the modified release formulation is suitable foradministration only once nightly, with reduced side effects ofobtundation and clinically significant respiratory depression occurringin adult patients treated with twice-nightly sodium oxybate.

A thirty ninth embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the immediate release portion comprisesgamma-hydroxybutyrate, and the modified release portion comprisesgamma-hydroxybutyrate coated with a coating comprising: a polymercarrying free carboxylic groups, and a hydrophobic compound having amelting point equal or greater than 40° C.

A fortieth embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the formulation yields a plasma concentration versustime curve when administered at a dose of 4.5 g, 6.0 g or 7.5 gapproximately two hours after a standardized evening meal substantiallyas depicted in FIG. 12 or FIG. 13 for the corresponding dose.

A forty fourth embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the formulation yields a plasma concentration versustime curve when administered at a dose of 4.5 g approximately two hoursafter a standardized evening meal substantially as depicted in FIG. 22 .

A forty fifth embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the formulation yields a dissolution profilesubstantially as depicted in FIG. 7 and FIG. 8 .

A forty sixth embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the formulation yields a dissolution profilesubstantially as depicted in FIG. 20 and FIG. 21 .

A forty seventh embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the modified release portion yields a dissolutionprofile substantially as depicted in FIG. 3 or FIG. 16 .

A forty eighth embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the formulation yields a dissolution profile betweenthe minimum and maximum values depicted in FIG. 25 and FIG. 26 .

A forty ninth embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the formulation yields a dissolution profile betweenthe minimum and maximum values depicted in FIG. 27 and FIG. 28 .

A fiftieth embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the formulation yields a dissolution profilesubstantially as shown in any one of FIGS. 29 through 89 .

A fifty first embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the formulation yields a plasma concentration versustime curve when administered at a dose of 4.5 g, 7.5 g or 9.0 gapproximately two hours after a standardized evening meal substantiallyas depicted in FIG. 90 for the corresponding dose.

A fifty second embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the formulation yields a dissolution profile betweenthe minimum and maximum values depicted in FIG. 26 and FIG. 28 .

A fifty third embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the formulation is defined based on the concentrationof gamma-hydroxybutyrate in the blood stream 8 hours afteradministration to a patient, and further wherein a 4.5 g dose achieves amean C_(8h) of from 4.7 to 9.0 microgram/mL.

A fifty fourth embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the formulation is defined based on the concentrationof gamma-hydroxybutyrate in the blood stream 8 hours afteradministration to a patient, and further wherein a 4.5 g dose achieves amean C_(8h) of from 3.5 to 4.7 microgram/mL.

A fifty fifth embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the formulation is defined based on the concentrationof gamma-hydroxybutyrate in the blood stream 8 hours afteradministration to a patient, and further wherein a 6.0 g dose achieves amean C_(8h) of from 6.3 to 16.7 microgram/mL.

A fifty sixth embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the formulation is defined based on the concentrationof gamma-hydroxybutyrate in the blood stream 8 hours afteradministration to a patient, and further wherein a 6.0 g dose achieves amean C_(8h) of from 7.3 to 15.4 microgram/mL.

A fifty seventh embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the formulation is defined based on the concentrationof gamma-hydroxybutyrate in the blood stream 8 hours afteradministration to a patient, and further wherein a 7.5 g dose achieves amean C_(8h) of from 13.0 to 40.3 microgram/mL.

A fifty eighth embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the formulation is defined based on the concentrationof gamma-hydroxybutyrate in the blood stream 8 hours afteradministration to a patient, and further wherein a 7.5 g dose achieves amean C_(8h) of from 24.7 to 37.2 microgram/mL.

A fifty ninth embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the formulation is defined based on the time requiredto reach maximum blood concentration of gamma-hydroxybutyrate to apatient, and further achieves a median T_(max) of 1.25 to 3.25 hourswhen administered once approximately two hours after a standardizedevening meal.

A sixtieth embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the formulation is defined based on the time requiredto reach maximum blood concentration of gamma-hydroxybutyrate to apatient, and further achieves a median T_(max) of 0.5 to 3.25 hours whenadministered once approximately two hours after a standardized eveningmeal.

A sixty first embodiment provides a modified release formulation ofgamma-hydroxybutyrate comprising immediate release and modified releaseportions, wherein the formulation produces a residual drug content inthe bloodstream similar to one observed after administration of an equaldose of an immediate release liquid solution of sodium oxybateadministered twice nightly.

A sixty second embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein theformulation is suitable for administration once-daily, and furtherwherein the formulation is resistant to alcohol-induced dose dumping.

A sixty third embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein theformulation releases at least 80% of its gamma-hydroxybutyrate at threehours when tested in a dissolution apparatus 2 according to USP 38 <711>in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at atemperature of 37° C. and a paddle speed of 75 rpm, and further whereinethanol concentrations from about 5% to about 20% does not change thedissolution profile.

A sixty fourth embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein theformulation releases at least 80% of its gamma-hydroxybutyrate at threehours when tested in a dissolution apparatus 2 according to USP 38 <711>in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at atemperature of 37° C. and a paddle speed of 75 rpm, and further whereinethanol concentrations from about 5% to about 20% does not change thedissolution profile.

A sixty fifth embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein theformulation releases from 10% to 65%, of its gamma-hydroxybutyrate atone hour and three hours when tested in a dissolution apparatus 2according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm, and further whereinethanol concentrations from about 5% to about 20% does not change thedissolution profile.

A sixty sixth embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein themodified release portion releases greater than 80% of itsgamma-hydroxybutyrate at three hours when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasicpotassium phosphate buffer pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm, and further wherein ethanol concentrations fromabout 5% to about 20% does not change the dissolution profile.

A sixty seventh embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein themodified release portion releases less than 20% of itsgamma-hydroxybutyrate at one hour when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm, and further whereinethanol concentrations from about 5% to about 20% does not change thedissolution profile.

A sixty eighth embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein themodified release portion provides a modified release profile, and therelease rate when measured using a first in vitro dissolution test inthe absence of ethanol and the release rate when using a second vitrodissolution test in the presence of about 5% to about 20% ethanol (v/v)are substantially the same, wherein, other than the absence or presenceethanol, the first in vitro dissolution test and the second in vitrodissolution test are the same.

A sixty ninth embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein themodified release portion releases greater than 80% of itsgamma-hydroxybutyrate at three hours in a dissolution test started in750 mL of 0.1N hydrochloric acid for 2 hours then switched to 950 mL0.05M monobasic potassium phosphate buffer adjusted to pH 6.8 at atemperature of 37° C. and a paddle speed of 75 rpm, and further whereinethanol concentrations from about 5% to about 20% does not change thedissolution profile.

A seventieth embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein theimmediate release portion releases greater than 80% of itsgamma-hydroxybutyrate at one hour when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm, and further whereinethanol concentrations from about 5% to about 20% does not change thedissolution profile.

A seventy first embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein a dose ofthe formulation achieves a relative bioavailability (RBA) of greaterthan 80% when compared to an equal dose of an immediate release liquidsolution of sodium oxybate administered at t₀ and t_(4h) in equallydivided doses, when administered approximately two hours after astandardized evening meal.

A seventy second embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein a dose ofthe formulation achieves a median T_(max) of 1.25 to 3.25 hours whenadministered once approximately two hours after a standardized eveningmeal.

A seventy third embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein a dose ofthe formulation achieves a median T_(max) of 0.5 to 3.25 hours whenadministered once approximately two hours after a standardized eveningmeal.

A seventy fourth embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein a dose ofthe formulation achieves a median T_(max) of about 1.25, 1.5, 1.75, 2,2.25, 2.5, 2.75, 3, or 3.25 hours when administered once approximatelytwo hours after a standardized evening meal.

A seventy fifth embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein a 7.5 gdose of the formulation achieves a mean AUC_(inf) of greater than 300hr·microgram/mL when administered once approximately two hours after astandardized evening meal. In some aspects, the mean AUC_(inf) isgreater than 340 hr·microgram/mL, 375 hr·microgram/mL, or greater than400 hr·microgram/mL.

A seventy sixth embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein a 7.5 gdose of the formulation achieves a mean C_(max) of greater than 70microgram/mL when administered once approximately two hours after astandardized evening meal.

A seventy seventh embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein a dose ofthe formulation achieves a mean AUC_(inf) of greater than 80% of themean AUC_(inf) provided by an equal dose of immediate release liquidsolution of sodium oxybate administered at t₀ and t_(4h) in equallydivided doses approximately two hours after a standardized evening meal,and a mean C_(8h) less than 95% of the mean C_(8h) provided by an equaldose of immediate release liquid solution of sodium oxybate administeredat t₀ and t_(4h) in equally divided doses approximately two hours aftera standardized evening meal.

A seventy eighth embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein a 4.5 gdose achieves a mean C_(8h) of from 4.7 to 9.0 microgram/mL whenadministered once approximately two hours after a standardized eveningmeal.

A seventy ninth embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein a 4.5 gdose achieves a mean C_(8h) of from 3.5 to 4.7 microgram/mL whenadministered once approximately two hours after a standardized eveningmeal.

An eightieth embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein a 6.0 gdose achieves a mean C_(8h) of from 6.3 to 16.7 microgram/mL whenadministered once approximately two hours after a standardized eveningmeal.

An eighty first embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein a 6.0 gdose achieves a mean C_(8h) of from 7.3 to 15.4 microgram/mL whenadministered once approximately two hours after a standardized eveningmeal.

An eighty second embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein a 7.5 gdose achieves a mean C_(8h) of from 13.0 to 40.3 microgram/mL whenadministered once approximately two hours after a standardized eveningmeal.

An eighty third embodiment provides a pharmaceutical formulationcomprising: an immediate release portion comprising a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate; and a modified release portioncomprising: microparticles comprising a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on the microparticlescomprising: a methacrylic acid polymer; and a hydrophobic compoundhaving a melting point equal or greater than 40° C., wherein a 7.5 gdose achieves a mean C_(8h) of from 24.7 to 37.2 microgram/mL whenadministered once approximately two hours after a standardized eveningmeal.

An eighty fourth embodiment provides a formulation comprising: amodified release portion comprising: a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on thegamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C.

An eighty fifth embodiment provides a formulation comprising: a modifiedrelease portion comprising: a pharmaceutically acceptable salt ofgamma-hydroxybutyrate; and at least one coating on thegamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the weight ratio of the hydrophobiccompound to the polymer carrying free carboxylic groups is from 0.4 to4.

An eighty sixth embodiment provides a formulation comprising: a modifiedrelease portion comprising: a pharmaceutically acceptable salt ofgamma-hydroxybutyrate; and at least one coating on thegamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the pharmaceutically acceptable salt ofgamma-hydroxybutyrate comprises a sodium salt of gamma-hydroxybutyricacid, a calcium salt of gamma-hydroxybutyric acid, a potassium salt ofgamma-hydroxybutyric acid, and/or a magnesium salt ofgamma-hydroxybutyric acid, and mixtures thereof. In some aspects, thepharmaceutically acceptable salt of gamma-hydroxybutyrate is a calciumsalt of gamma-hydroxybutyric acid. In another aspect, thepharmaceutically acceptable salt of comprises calcium and magnesium saltof gamma-hydroxybutyric acid. In yet another aspect, thepharmaceutically acceptable salt of comprises calcium, potassium, andmagnesium salt of gamma-hydroxybutyric acid.

An eighty seventh embodiment provides a formulation comprising: amodified release portion comprising: a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on thegamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., further comprising microcrystalline cellulose. Insome aspects, the microcrystalline cellulose is present at about 10%w/w-15% w/w.

An eighty eighth embodiment provides a formulation comprising: amodified release portion comprising: a pharmaceutically acceptable saltof gamma-hydroxybutyrate; and at least one coating on thegamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., further comprising a layer of hydroxypropylcellulose.

An eighty ninth embodiment provides a formulation comprising: a modifiedrelease portion comprising: a pharmaceutically acceptable salt ofgamma-hydroxybutyrate; and at least one coating on thegamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the polymer carrying free carboxylic groupshas a pH-dependent solubility.

A ninetieth embodiment provides a formulation comprising: a modifiedrelease portion comprising: a pharmaceutically acceptable salt ofgamma-hydroxybutyrate; and at least one coating on thegamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the polymer carrying free carboxylic groupsis selected from the group consisting of (meth)acrylic acid/alkyl(meth)acrylate copolymers, methacrylic acid and methylmethacrylatecopolymers, methacrylic acid and ethyl acrylate copolymers, methacrylicacid copolymers type A, B or C, cellulose derivatives carrying freecarboxylic groups, preferably cellulose acetate phthalate, celluloseacetate succinate, hydroxypropyl methyl cellulose phthalate,carboxymethylethyl cellulose, cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetatephthalate, zein, shellac, alginate, and mixtures thereof.

A ninety first embodiment provides a formulation comprising: a modifiedrelease portion comprising: a pharmaceutically acceptable salt ofgamma-hydroxybutyrate; and at least one coating on thegamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the polymer carrying free carboxylic groupscomprises a methacrylic acid copolymer. In some aspects, the methacrylicacid copolymer is selected from the group consisting of poly(methacrylic acid, methyl methacrylate) 1:1, poly (methacrylic acid,ethyl acrylate) 1:1, poly (methacrylic acid, methyl methacrylate) 1:2,and mixtures thereof. In additional aspects, the methacrylic acidcopolymer comprises poly(methacrylic acid, ethyl acrylate) 1:1.

A ninety second embodiment provides a formulation comprising: a modifiedrelease portion comprising: a pharmaceutically acceptable salt ofgamma-hydroxybutyrate; and at least one coating on thegamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the coating is from 10 to 50% of the weightof the modified release portion.

A ninety third embodiment provides a formulation comprising: a modifiedrelease portion comprising: a pharmaceutically acceptable salt ofgamma-hydroxybutyrate; and at least one coating on thegamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., further comprising an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate.In some aspects, the formulation further comprises xanthan gum,carrageenan gum, gellan gum, guar gum, sodium alginate, calciumalginate, agar, sodium carboxymethyl cellulose, microcrystallinecellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ormixtures thereof. In at least one aspect, the formulation comprises guargum. For example, the guar gum is present at 1% to 15% by weight of theformulation.

A ninety fourth embodiment provides a formulation comprising: a modifiedrelease portion comprising: a pharmaceutically acceptable salt ofgamma-hydroxybutyrate; and at least one coating on thegamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation is a dry particulateformulation or a powdered formulation.

A ninety fifth embodiment provides a formulation comprising: a modifiedrelease portion comprising: a pharmaceutically acceptable salt ofgamma-hydroxybutyrate; and at least one coating on thegamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation comprises 4.5 g, 6.0 g, 7.5g, or 9.0 g of gamma-hydroxybutyrate.

A ninety sixth embodiment provides a formulation comprising: a modifiedrelease portion comprising: a pharmaceutically acceptable salt ofgamma-hydroxybutyrate; and at least one coating on thegamma-hydroxybutyrate comprising: a polymer carrying free carboxylicgroups; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation is suitable to be orallyadministered once-nightly.

A ninety seventh embodiment provides a formulation ofgamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C.

A ninety eighth embodiment provides a formulation ofgamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the weight ratio of the hydrophobiccompound to the methacrylic acid copolymer is from 0.4 to 4.

A ninety ninth embodiment provides a formulation ofgamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the ratio of gamma-hydroxybutyrate in theimmediate release portion and the modified release portion is from 10/90to 65/35.

A one hundredth embodiment provides a formulation ofgamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the pharmaceutically acceptable salt ofgamma-hydroxybutyrate is selected from a sodium salt ofgamma-hydroxybutyric acid, a calcium salt of gamma-hydroxybutyric acid,a potassium salt of gamma-hydroxybutyric acid, and/or a magnesium saltof gamma-hydroxybutyric acid. In some aspects, the pharmaceuticallyacceptable salt of gamma-hydroxybutyrate is a calcium salt ofgamma-hydroxybutyric acid.

A one hundred and first embodiment provides a formulation ofgamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the microparticles further comprise a layerof hydroxypropyl cellulose.

A one hundred and second embodiment provides a formulation ofgamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the methacrylic acid copolymer is selectedfrom the group consisting of (meth)acrylic acid/alkyl (meth)acrylatecopolymers, methacrylic acid and methylmethacrylate copolymers,methacrylic acid and ethyl acrylate copolymers, methacrylic acidcopolymers type A, B or C, and mixtures thereof. In some aspects, themethacrylic acid copolymer is selected from the group consisting of poly(methacrylic acid, methyl methacrylate) 1:1, poly (methacrylic acid,ethyl acrylate) 1:1, poly (methacrylic acid, methyl methacrylate) 1:2,and mixtures thereof. In at least one aspect, the methacrylic acidcopolymers comprise poly(methacrylic acid, ethyl acrylate) 1:1.

A one hundred and third embodiment provides a formulation ofgamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the coating is from 10 to 50% of the weightof the microparticles.

A one hundred and fourth embodiment provides a formulation ofgamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., further comprising xanthan gum, carrageenan gum,gellan gum, guar gum, sodium alginate, calcium alginate, agar, sodiumcarboxymethyl cellulose, microcrystalline cellulose, hydroxyethylcellulose, hydroxypropylmethyl cellulose, or mixtures thereof. In someaspects, the formulation comprises guar gum. In at least one aspect, theguar gum is present at 1% to 15% by weight of the formulation.

A one hundred and fifth embodiment provides a formulation ofgamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation is a dry particulateformulation or a powdered formulation.

A one hundred and sixth embodiment provides a formulation ofgamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation comprises 4.5 g, 6.0 g, 7.5g, or 9.0 g of the pharmaceutically acceptable salt ofgamma-hydroxybutyrate.

A one hundred and seventh embodiment provides a formulation ofgamma-hydroxybutyrate comprising: an immediate release portioncomprising a pharmaceutically acceptable salt of gamma-hydroxybutyrate;a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidcopolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation is suitable to be orallyadministered once-daily. In some aspects, the formulation is suitable tobe orally administered once-nightly.

A one hundred and eighth embodiment provides a formulation comprising: amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising a methacrylic acidcopolymer.

A one hundred and ninth embodiment provides a formulation comprising: amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising a methacrylic acidcopolymer, wherein the pharmaceutically acceptable salt ofgamma-hydroxybutyrate is selected from a sodium salt ofgamma-hydroxybutyric acid, a calcium salt of gamma-hydroxybutyric acid,a potassium salt of gamma-hydroxybutyric acid, and/or a magnesium saltof gamma-hydroxybutyric acid. In some aspects, the pharmaceuticallyacceptable salt of gamma-hydroxybutyrate is a calcium salt ofgamma-hydroxybutyric acid.

A one hundred and tenth embodiment provides a formulation comprising: amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising a methacrylic acidcopolymer, wherein the microparticles further comprise a layer ofhydroxypropyl cellulose.

A one hundred and eleventh embodiment provides a formulation comprising:a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising a methacrylic acidcopolymer, wherein the methacrylic acid copolymer is selected from thegroup consisting of (meth)acrylic acid/alkyl (meth)acrylate copolymers,methacrylic acid and methylmethacrylate copolymers, methacrylic acid andethyl acrylate copolymers, methacrylic acid copolymers type A, B or C,and mixtures thereof. In some aspects, the methacrylic acid copolymer isselected from the group consisting of poly (methacrylic acid, methylmethacrylate) 1:1, poly (methacrylic acid, ethyl acrylate) 1:1, poly(methacrylic acid, methyl methacrylate) 1:2, and mixtures thereof. In atleast one aspect, the methacrylic acid copolymers comprisepoly(methacrylic acid, ethyl acrylate) 1:1.

A one hundred and twelfth embodiment provides a formulation comprising:a modified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising a methacrylic acidcopolymer, wherein the coating is from 10 to 50% of the weight of themicroparticles.

A one hundred and thirteenth embodiment provides a method of treatingcataplexy in narcolepsy or excessive daytime sleepiness (“EDS”) innarcolepsy, the method comprising administering a formulation ofgamma-hydroxybutyrate once-daily.

A one hundred and fourteenth embodiment provides a method of treatingcataplexy in narcolepsy or excessive daytime sleepiness (“EDS”) innarcolepsy, the method comprising administering a formulation ofgamma-hydroxybutyrate once-nightly.

A one hundred and fifteenth embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation is suitable foradministration once-daily.

A one hundred and sixteenth embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation releases at least 80% ofits gamma-hydroxybutyrate at three hours when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasicpotassium phosphate buffer pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm.

A one hundred and seventeenth embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the formulation releases from 10% to 65%,of its gamma-hydroxybutyrate at one hour and three hours when tested ina dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm.

A one hundred and eighteenth embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the modified release portion releasesgreater than 80% of its gamma-hydroxybutyrate at three hours when testedin a dissolution apparatus 2 according to USP 38 <711> in 900 mL of0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm.

A one hundred and nineteenth embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the modified release portion releases lessthan 20% of its gamma-hydroxybutyrate at one hour when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm.

A one hundred and twentieth embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the modified release portion releasesgreater than 80% of its gamma-hydroxybutyrate at three hours in adissolution test started in 750 mL of 0.1N hydrochloric acid for 2 hoursthen switched to 950 mL 0.05M monobasic potassium phosphate bufferadjusted to pH 6.8 at a temperature of 37° C. and a paddle speed of 75rpm.

A one hundred and twenty first embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the immediate release portion releasesgreater than 80% of its gamma-hydroxybutyrate at one hour when tested ina dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm.

A one hundred and twenty second embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a dose of the formulation achieves arelative bioavailability (RBA) of greater than 80% when compared to anequal dose of an immediate release liquid solution of sodium oxybateadministered at t₀ and t_(4h) in equally divided doses, whenadministered approximately two hours after a standardized evening meal.

A one hundred and twenty third embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a dose of the formulation achieves a medianT_(max) of 1.25 to 3.25 hours when administered once approximately twohours after a standardized evening meal.

A one hundred and twenty fourth embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a dose of the formulation achieves a medianT_(max) of 0.5 to 3.25 hours when administered once approximately twohours after a standardized evening meal.

A one hundred and twenty fifth embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a dose of the formulation achieves a medianT_(max) of about 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, or 3.25 hourswhen administered once approximately two hours after a standardizedevening meal.

A one hundred and twenty sixth embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 7.5 g dose of the formulation achieves amean AUC_(inf) of greater than 300 hr·microgram/mL when administeredonce approximately two hours after a standardized evening meal. In someaspects, the mean AUC_(inf) is greater than 340 hr·microgram/mL, greaterthan 375 hr·microgram/mL, or greater than 400 hr·microgram/mL.

A one hundred and twenty seventh embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 7.5 g dose of the formulation achieves amean C_(max) of greater than 70 microgram/mL when administered onceapproximately two hours after a standardized evening meal.

A one hundred and twenty eighth embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a dose of the formulation achieves a meanAUC_(inf) of greater than 80% of the mean AUC_(inf) provided by an equaldose of immediate release liquid solution of sodium oxybate administeredat t₀ and t_(4h) in equally divided doses approximately two hours aftera standardized evening meal, and a mean C_(8h) less than 95% of the meanC_(8h) provided by an equal dose of immediate release liquid solution ofsodium oxybate administered at t₀ and t_(4h) in equally divided dosesapproximately two hours after a standardized evening meal.

A one hundred and twenty ninth embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 4.5 g dose achieves a mean C_(8h) of from4.7 to 9.0 microgram/mL when administered once approximately two hoursafter a standardized evening meal.

A one hundred and thirtieth embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 4.5 g dose achieves a mean C_(8h) of from3.5 to 4.7 microgram/mL when administered once approximately two hoursafter a standardized evening meal.

A one hundred and thirty first embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 6.0 g dose achieves a mean C_(8h) of from6.3 to 16.7 microgram/mL when administered once approximately two hoursafter a standardized evening meal.

A one hundred and thirty second embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 6.0 g dose achieves a mean C_(8h) of from7.3 to 15.4 microgram/mL when administered once approximately two hoursafter a standardized evening meal.

A one hundred and thirty third embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 7.5 g dose achieves a mean C_(8h) of from13.0 to 40.3 microgram/mL when administered once approximately two hoursafter a standardized evening meal.

A one hundred and thirty fourth embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein a 7.5 g dose achieves a mean C_(8h) of from24.7 to 37.2 microgram/mL when administered once approximately two hoursafter a standardized evening meal.

A one hundred and thirty fifth embodiment provides a pharmaceuticalformulation comprising: an immediate release portion comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and amodified release portion comprising: microparticles comprising apharmaceutically acceptable salt of gamma-hydroxybutyrate; and at leastone coating on the microparticles comprising: a methacrylic acidpolymer; and a hydrophobic compound having a melting point equal orgreater than 40° C., wherein the composition produces a residual drugcontent in the bloodstream similar to one observed after administrationof an equal dose of an immediate release liquid solution of sodiumoxybate administered twice nightly.

A one hundred and thirty sixth embodiment provides a formulationcomprising a pharmaceutically acceptable salt of gamma-hydroxybutyratein an immediate release portion and a modified release portion, whereinthe modified release portion comprises microparticles having at leastone coating comprising a methacrylic acid copolymer, and wherein theformulation is suitable for administration once-daily.

A one hundred and thirty seventh embodiment provides a formulationcomprising a pharmaceutically acceptable salt of gamma-hydroxybutyratein an immediate release portion and a modified release portion, whereinthe modified release portion comprises microparticles having at leastone coating comprising a methacrylic acid copolymer, wherein a dose ofthe formulation achieves a mean AUC_(inf) of greater than 80% of themean AUC_(inf) provided by an equal dose of immediate release liquidsolution of sodium oxybate administered at t₀ and t_(4h) in equallydivided doses approximately two hours after a standardized evening meal.In some aspects, a 7.5 g dose of the formulation achieves a meanAUC_(inf) of greater than 340 hr·microgram/mL, greater than 375hr·microgram/mL, or greater than 400 hr·microgram/mL.

A one hundred and thirty eighth embodiment provides a formulationcomprising a pharmaceutically acceptable salt of gamma-hydroxybutyratein an immediate release portion and a modified release portion, whereinthe modified release portion comprises microparticles having at leastone coating comprising a methacrylic acid copolymer, wherein a dose ofthe formulation achieves a median T_(max) of 1.25 to 3.25 hours whenadministered once approximately two hours after a standardized eveningmeal.

A one hundred and thirty ninth embodiment provides a formulationcomprising a pharmaceutically acceptable salt of gamma-hydroxybutyratein an immediate release portion and a modified release portion, whereinthe modified release portion comprises microparticles having at leastone coating comprising a methacrylic acid copolymer, wherein a dose ofthe formulation achieves a median T_(max) of 0.5 to 3.25 hours whenadministered once approximately two hours after a standardized eveningmeal.

A one hundred and fortieth embodiment provides a formulation comprisinga pharmaceutically acceptable salt of gamma-hydroxybutyrate in animmediate release portion and a modified release portion, wherein themodified release portion comprises microparticles having at least onecoating comprising a methacrylic acid copolymer, wherein a dose of theformulation achieves a median T_(max) of about 1.25, 1.5, 1.75, 2, 2.25,2.5, 2.75, 3, or 3.25 hours when administered once approximately twohours after a standardized evening meal.

A one hundred and forty first embodiment provides a formulationcomprising a pharmaceutically acceptable salt of gamma-hydroxybutyratein an immediate release portion and a modified release portion, whereinthe modified release portion comprises microparticles having at leastone coating comprising a methacrylic acid copolymer, wherein a 7.5 gdose of the formulation achieves a mean C_(max) of greater than 70microgram/mL when administered once approximately two hours after astandardized evening meal.

A one hundred and forty second embodiment provides a formulationcomprising a pharmaceutically acceptable salt of gamma-hydroxybutyratein an immediate release portion and a modified release portion, whereinthe modified release portion comprises microparticles having at leastone coating comprising a methacrylic acid copolymer, wherein a 4.5 gdose achieves a mean C_(8h) of from 4.7 to 9.0 microgram/mL whenadministered once approximately two hours after a standardized eveningmeal.

A one hundred and forty third embodiment provides a formulationcomprising a pharmaceutically acceptable salt of gamma-hydroxybutyratein an immediate release portion and a modified release portion, whereinthe modified release portion comprises microparticles having at leastone coating comprising a methacrylic acid copolymer, wherein a 4.5 gdose achieves a mean C_(8h) of from 3.5 to 4.7 microgram/mL whenadministered once approximately two hours after a standardized eveningmeal.

A one hundred and forty fourth embodiment provides a formulationcomprising a pharmaceutically acceptable salt of gamma-hydroxybutyratein an immediate release portion and a modified release portion, whereinthe modified release portion comprises microparticles having at leastone coating comprising a methacrylic acid copolymer, wherein a 6.0 gdose achieves a mean C_(8h) of from 6.3 to 16.7 microgram/mL whenadministered once approximately two hours after a standardized eveningmeal.

A one hundred and forty fifth embodiment provides a formulationcomprising a pharmaceutically acceptable salt of gamma-hydroxybutyratein an immediate release portion and a modified release portion, whereinthe modified release portion comprises microparticles having at leastone coating comprising a methacrylic acid copolymer, wherein a 6.0 gdose achieves a mean C_(8h) of from 7.3 to 15.4 microgram/mL whenadministered once approximately two hours after a standardized eveningmeal.

A one hundred and forty sixth embodiment provides a formulationcomprising a pharmaceutically acceptable salt of gamma-hydroxybutyratein an immediate release portion and a modified release portion, whereinthe modified release portion comprises microparticles having at leastone coating comprising a methacrylic acid copolymer, wherein a 7.5 gdose achieves a mean C_(8h) of from 13.0 to 40.3 microgram/mL whenadministered once approximately two hours after a standardized eveningmeal.

A one hundred and forty seventh embodiment provides a formulationcomprising a pharmaceutically acceptable salt of gamma-hydroxybutyratein an immediate release portion and a modified release portion, whereinthe modified release portion comprises microparticles having at leastone coating comprising a methacrylic acid copolymer, wherein a 7.5 gdose achieves a mean C_(8h) of from 24.7 to 37.2 microgram/mL whenadministered once approximately two hours after a standardized eveningmeal.

A one hundred and forty eighth embodiment provides a formulationcomprising a pharmaceutically acceptable salt of gamma-hydroxybutyratein an immediate release portion and a modified release portion, whereinthe modified release portion comprises microparticles having at leastone coating comprising a methacrylic acid copolymer, wherein the 7.5 gdose of the formulation achieves a mean C_(8h) from 50% to 130% of themean C_(8h) provided by an equal dose of an immediate release liquidsolution of sodium oxybate administered at to and t_(4h) in equallydivided doses approximately two hours after a standardized evening meal.In some aspects, the mean C_(8h) achieved by the formulation is from 60%to 90% of the mean C_(8h) provided by the immediate release liquidsolution of sodium oxybate.

A one hundred and forty ninth embodiment provides a formulationcomprising a pharmaceutically acceptable salt of gamma-hydroxybutyratein an immediate release portion and a modified release portion, whereinthe modified release portion comprises microparticles having at leastone coating comprising a methacrylic acid copolymer, wherein a dose ofthe formulation achieves a relative bioavailability (RBA) of greaterthan 80% when compared to an equal dose of an immediate release liquidsolution of sodium oxybate administered at t₀ and t_(4h) in equallydivided doses, when administered approximately two hours after astandardized evening meal.

A one hundred and fiftieth embodiment provides a formulation comprisinga pharmaceutically acceptable salt of gamma-hydroxybutyrate in animmediate release portion and a modified release portion, wherein themodified release portion comprises microparticles having at least onecoating comprising a methacrylic acid copolymer, wherein the dose is a4.5 g, 6 g, 7.5 g, or 9 g dose of the formulation.

A one hundred and fifty first embodiment provides a pharmaceuticalformulation comprising: particles of gamma-hydroxybutyrate comprising acore and a coating deposited on the core, wherein the coating inhibitsthe release of gamma-hydroxybutyrate, and wherein the coating comprisesa polymer that is selected from methylmethacrylate polymers.

A one hundred and fifty second embodiment provides a pharmaceuticalformulation comprising: particles of gamma-hydroxybutyrate comprising acore and a coating deposited on the core, wherein the coating inhibitsthe release of gamma-hydroxybutyrate, and wherein the coating comprisesa polymer that is selected from methylmethacrylate polymers, furthercomprising ethylcellulose or microcrystalline cellulose.

A one hundred and fifty third embodiment provides a pharmaceuticalformulation comprising: particles of gamma-hydroxybutyrate comprising acore and a coating deposited on the core, wherein the coating inhibitsthe release of gamma-hydroxybutyrate, and wherein the coating comprisesa polymer that is selected from methylmethacrylate polymers, furthercomprising cellulose derivatives carrying free carboxylic groups.

A one hundred and fifty fourth embodiment provides a pharmaceuticalformulation comprising: particles of gamma-hydroxybutyrate comprising acore and a coating deposited on the core, wherein the coating inhibitsthe release of gamma-hydroxybutyrate, and wherein the coating comprisesa polymer that is selected from methylmethacrylate polymers, furthercomprising cellulose acetate phthalate, cellulose acetate succinate,hydroxypropyl methyl cellulose phthalate, carboxymethylethyl cellulose,cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetatesuccinate, polyvinyl acetate phthalate, zein, shellac, alginate, andmixtures thereof.

A one hundred and fifty fifth embodiment provides a pharmaceuticalformulation comprising: particles of gamma-hydroxybutyrate comprising acore and a coating deposited on the core, wherein the coating inhibitsthe release of gamma-hydroxybutyrate, and wherein the coating comprisesa polymer that is selected from methylmethacrylate polymers comprisingEudragit™ L100, or Eudragit™ L100-55, or Eudragit™ S100.

A one hundred and fifty sixth embodiment provides a pharmaceuticalformulation comprising: particles of gamma-hydroxybutyrate comprising acore and a coating deposited on the core, wherein the coating inhibitsthe release of gamma-hydroxybutyrate, and wherein the coating comprisesa polymer that is selected from methylmethacrylate polymers, wherein thecoating comprises ethyl acrylate.

A one hundred and fifty seventh embodiment provides a pharmaceuticalformulation comprising: particles of gamma-hydroxybutyrate comprising acore and a coating deposited on the core, wherein the coating inhibitsthe release of gamma-hydroxybutyrate, and wherein the coating comprisesa polymer that is selected from methylmethacrylate polymers comprisingpoly (methacrylic acid, methyl methacrylate) 1:1, poly (methacrylicacid, ethyl acrylate) 1:1, or poly (methacrylic acid, methylmethacrylate).

A one hundred and fifty eighth embodiment provides a pharmaceuticalformulation comprising: particles of gamma-hydroxybutyrate comprising acore and a coating deposited on the core, wherein the coating inhibitsthe release of gamma-hydroxybutyrate, and wherein the coating comprisesa polymer that is selected from methylmethacrylate polymers, wherein thecoating comprises a polymer that is selected from methylmethacrylatepolymers having a pH-dependent solubility.

A one hundred and fifty ninth embodiment provides a pharmaceuticalformulation comprising: particles of gamma-hydroxybutyrate comprising acore and a coating deposited on the core; and immediate releaseparticles that release at least 80% or 90% of its gamma-hydroxybutyrateat 3 hours, 2 hours, 1 hour, 0.5 hours, or 0.25 hours, wherein thecoating inhibits the release of gamma-hydroxybutyrate, and wherein thecoating comprises a polymer that is selected from methylmethacrylatepolymers.

A one hundred and sixtieth embodiment of the present invention providesa modified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions, wherein a7.5 g dose of the formulation has been shown to achieve a mean AUC_(inf)of greater than 245, 300, 325, 340, 375, 400, 425, or 450hr×microgram/mL, most preferably greater than 340 hr×microgram/mL.

A one hundred and sixty first principal embodiment of the presentinvention provides a modified release formulation ofgamma-hydroxybutyrate, preferably comprising immediate release andmodified release portions, wherein a 7.5 g dose of the formulation hasbeen shown to achieve a mean AUC_(inf) of greater than 245, 265, 285,300, 315, 325, 340, 350, 375, 400, 425, or 450 hr×microgram/mL, mostpreferably greater than 340 hr×microgram/mL, and a mean C_(8h) that isfrom 50% to 130%, from 60% to 130%, from 70% to 130%, from 75% to 125%,from 80% to 125%, from 80 to 120%, from 90% to 110%, from 50% to 95%,from 60% to 90%, most preferably from 60% to 90% or 60% to 130% of themean C_(8h) provided by an equal dose of an immediate release liquidsolution of sodium oxybate (e.g. Xyrem®) administered at to and t_(4h)in equally divided doses approximately two hours after a standardizedevening meal.

A one hundred and sixty second principal embodiment of the presentinvention provides a modified release formulation ofgamma-hydroxybutyrate, preferably comprising immediate release andmodified release portions, wherein the formulation releases (a) at least80% or 90% of its gamma-hydroxybutyrate at 3 hours, 2 hours, 1 hour, 0.5hours, or 0.25 hours, preferably 1 hour, when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasicpotassium phosphate buffer pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm, and (b) from 10 to 65%, from 15 to 60%, from 20to 55%, from 25 to 55%, from 30 to 55%, from 35 to 55%, from 40 to 55%,from 40 to 60%, or from 45 to 55%, preferably from 40% to 60%, of itsgamma-hydroxybutyrate at one hour and three hours when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm.

A one hundred and sixty third principal embodiment of the presentinvention provides a modified release formulation ofgamma-hydroxybutyrate, comprising immediate release and modified releaseportions, wherein (a) the formulation releases at least 80% or 90% ofits gamma-hydroxybutyrate at 3 hours, 2 hours, 1 hour, 0.5 hours, or0.25 hours, preferably 1 hour, when tested in a dissolution apparatus 2according to USP 38 <711> in 900 mL of 0.05M monobasic potassiumphosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of75 rpm, (b) the formulation releases from 10 to 65%, from 15 to 60%,from 20 to 55%, from 25 to 55%, from 30 to 55%, from 35 to 55%, from 40to 55%, from 40 to 60%, or from 45 to 55%, preferably from 40% to 60%,of its gamma-hydroxybutyrate at one hour and at three hours when testedin a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm, and (c) the modified release portion preferably releases greaterthan 80% or 90% of its gamma-hydroxybutyrate at 3 hours in a dissolutiontest started in 750 mL of 0.1N hydrochloric acid for 2 hours thenswitched to 950 mL 0.05M monobasic potassium phosphate buffer adjustedto pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm.

A one hundred and sixty fourth embodiment of the present inventionprovides a modified release formulation of gamma-hydroxybutyrate,comprising immediate release and modified release portions, wherein (a)the formulation releases at least 80% or 90% of itsgamma-hydroxybutyrate at 3 hours, 2 hours, 1 hour, 0.5 hours, or 0.25hours, preferably 1 hour, when tested in a dissolution apparatus 2according to USP 38 <711> in 900 mL of 0.05M monobasic potassiumphosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of75 rpm, (b) the formulation releases from 10 to 65%, from 15 to 60%,from 20 to 55%, from 25 to 55%, from 30 to 55%, from 35 to 55%, from 40to 55%, from 40 to 60%, or from 45 to 55%, preferably from 40% to 60%,of its gamma-hydroxybutyrate at one hour and at three hours when testedin a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm, (c) the formulation releases greater than 60%, 70%, or 80%,preferably greater than 80%, of its gamma-hydroxybutyrate at 10 hourswhen tested in a dissolution apparatus 2 according to USP 38 <711> in900 mL of 0.1N hydrochloric acid at a temperature of 37° C. and a paddlespeed of 75 rpm, and (d) the modified release portion releases greaterthan 80% of its gamma-hydroxybutyrate at 3 hours in a dissolution teststarted in 750 mL of 0.1N hydrochloric acid for 2 hours then switched to950 mL 0.05M monobasic potassium phosphate buffer adjusted to pH 6.8 ata temperature of 37° C. and a paddle speed of 75 rpm.

A one hundred and sixty fifth embodiment of the present inventionprovides a modified release formulation of gamma-hydroxybutyrate,comprising immediate release and modified release portions, wherein (a)a 7.5 g dose of the formulation has been shown to achieve a meanAUC_(inf) of greater than 245, 300, 325, 340, 375, 400, 425, or 450hr×microgram/mL, preferably 340 hr×microgram/mL, and a mean C_(8h) thatis from 50% to 130%, from 60% to 130%, from 70% to 130%, from 75% to125%, from 80% to 125%, from 80 to 120%, from 90% to 110%, from 50% to95%, or from 60% to 90%, preferably from 60% to 90% or from 60% to 130%,of the mean C_(8h) provided by an equal dose of an immediate releaseliquid solution of gamma-hydroxybutyrate (e.g. Xyrem®) administered att₀ and t_(4h) in equally divided doses approximately two hours after astandardized evening meal, and (b) the formulation releases (i) at least80% or 90% of its gamma-hydroxybutyrate at 3 hours, 2 hours, 1 hour, 0.5hours, or 0.25 hours, preferably 1 hour, when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasicpotassium phosphate buffer pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm, and (ii) from 10 to 65%, from 15 to 60%, from 20to 55%, from 25 to 55%, from 30 to 55%, from 35 to 55%, from 40 to 55%,from 40 to 60%, or from 45 to 55%, preferably from 40% to 60%, of itsgamma-hydroxybutyrate at one hour and three hours when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm, and (c) the modified release portion releases greater than 80% ofits gamma-hydroxybutyrate at 3 hours in a dissolution test started in750 mL of 0.1N hydrochloric acid for 2 hours then switched to 950 mL0.05M monobasic potassium phosphate buffer adjusted to pH 6.8 at atemperature of 37° C. and a paddle speed of 75 rpm.

A one hundred and sixty sixth embodiment of the present inventionprovides a modified release formulation of gamma-hydroxybutyratecomprising immediate release and modified release portions, wherein: (a)said immediate release portion releases greater than 80% or 90% of itsgamma-hydroxybutyrate at one hour when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm; (b) said modifiedrelease portion releases less than 20% or 10% of itsgamma-hydroxybutyrate at one hour when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm; and (c) saidmodified release portion releases greater than 80% or 90% of itsgamma-hydroxybutyrate at three hours, two hours or one hour, when testedin a dissolution apparatus 2 according to USP 38 <711> in 900 mL of0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm.

A one hundred and sixty seventh embodiment of the present inventionprovides a modified release formulation of gamma-hydroxybutyratecomprising immediate release and modified release portions, wherein: (a)said immediate release portion releases greater than 80% or 90% of itsgamma-hydroxybutyrate at one hour, two hours, or three hours when testedin a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm; (b) said modified release portion releases less than 20% or 10% ofits gamma-hydroxybutyrate at one hour when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.1N hydrochloricacid at a temperature of 37° C. and a paddle speed of 75 rpm; (c) saidmodified release portion releases greater than 80% or 90% of itsgamma-hydroxybutyrate at three hours, two hours, or one hour, whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm; and (d) said modified releaseportion releases greater than 80% or 90% of its gamma-hydroxybutyrate at3 hours in a dissolution test started in 750 mL of 0.1N hydrochloricacid for 2 hours then switched to 950 mL 0.05M monobasic potassiumphosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm.

A one hundred and sixty eighth embodiment of the present inventionprovides a modified release formulation of gamma-hydroxybutyrate,preferably comprising immediate release and modified release portions,wherein a 4.5 g, 6 g, 7.5 g, and 9 g dose of the formulation has beenshown to achieve a relative bioavailability (RBA) of greater than 80%,85% or 90% when compared to an equal dose of an immediate release liquidsolution of sodium oxybate administered at t₀ and t_(4h) in equallydivided doses, when administered approximately two hours after astandardized evening meal. The relative bioavailability is even higherwith larger doses, and with a 6.0 g or 7.5 g or 9.0 g dose is preferablygreater than 90, 95 or 100% when compared to an equal dose of animmediate release liquid solution of sodium oxybate administered at t₀and t_(4h) in equally divided doses, when administered approximately twohours after a standardized evening meal.

A one hundred and sixty ninth embodiment of the present inventionprovides a modified release formulation of gamma-hydroxybutyrate,wherein a 4.5 g and a 9 g dose of the formulation has been shown toachieve a relative bioavailability (RBA) of greater than 80% whencompared to an equal dose of an immediate release liquid solution ofsodium oxybate administered at t₀ and t_(4h) in equally divided doses,when administered approximately two hours after a standardized eveningmeal.

A one hundred and seventieth principal embodiment of the presentinvention provides a modified release formulation ofgamma-hydroxybutyrate, preferably comprising immediate release andmodified release portions, that yields a plasma concentration versustime curve when administered once nightly at a strength of 4.5 g, 6.0 g,or 7.5 g approximately two hours after a standardized evening mealsubstantially as depicted in FIG. 12 or FIG. 13 for the correspondingstrength.

A one hundred and seventy first principal embodiment of the presentinvention provides a modified release formulation ofgamma-hydroxybutyrate, preferably comprising immediate release andmodified release portions, that yields a plasma concentration versustime curve when administered once nightly at a strength of 4.5 gapproximately two hours after a standardized evening meal substantiallyas depicted in FIG. 22 .

A one hundred and seventy second principal embodiment of the presentinvention provides a modified release formulation ofgamma-hydroxybutyrate, preferably comprising immediate release andmodified release portions, which yields a dissolution profilesubstantially as depicted in FIG. 7 and FIG. 8 .

A one hundred and seventy third principal embodiment of the presentinvention provides a modified release formulation ofgamma-hydroxybutyrate, preferably comprising immediate release andmodified release portions, which yields a dissolution profilesubstantially as depicted in FIG. 20 and FIG. 21 .

A one hundred and seventy fourth embodiment of the present inventionprovides a modified release formulation of gamma-hydroxybutyrate,preferably comprising immediate release and modified release portionsthat yields a dissolution profile substantially as depicted in FIG. 3 or16 .

A one hundred and seventy fifth embodiment of the invention provides amodified release formulation of gamma-hydroxybutyrate, comprisingimmediate release and modified release portions that yields adissolution profile between the minimum and maximum values depicted inFIG. 25 and FIG. 26 .

A one hundred and seventy sixth embodiment of the invention provides amodified release formulation of gamma-hydroxybutyrate, comprisingimmediate release and modified release portions that yields adissolution profile between the minimum and maximum values depicted inFIG. 27 and FIG. 28 .

A one hundred and seventy seventh embodiment of the invention provides amodified release formulation of gamma-hydroxybutyrate yielding adissolution profile substantially as shown in any one of FIGS. 29through 89 .

A one hundred and seventy eighth embodiment of the present inventionprovides a modified release formulation of gamma-hydroxybutyrate,preferably comprising immediate release and modified release portions,that yields a plasma concentration versus time curve when administeredonce nightly at a strength of 4.5 g, 7.5 g or 9.0 g approximately twohours after a standardized evening meal substantially as depicted inFIG. 90 for the corresponding strength.

A one hundred and seventy ninth embodiment of the present inventionprovides a pharmaceutical composition storage and administration systemcomprising: at least seven nightly dose packets, each nightly dosepacket operable to contain a single once daily dosage of a compositioncomprising gamma-hydroxybutyrate; one or more packet containers, eachpacket container operable to receive up to seven nightly dose packets; amixing cup comprising a lid, a first fill line, and a second fill line;a mixing cup receptacle comprising a cup retaining portion operable toreceive the mixing cup; and a carton operable to removably receive theone or more packet containers with up to seven packets in each containerand the mixing cup receptacle with the mixing cup.

A one hundred and eightieth embodiment of the present invention providesa pharmaceutical composition storage and administration system, whereineach nightly dose packet contains a once daily dosage of 4.5 g, 6 g,7.5, g, or 9 g gamma-hydroxybutyrate.

A one hundred and eighty first embodiment of the present inventionprovides a pharmaceutical composition storage and administration system,wherein the carton is operable to removably receive one packet containerwith seven nightly dose packets and the mixing cup receptacle with themixing cup to provide a 7-day supply of the composition.

A one hundred and eighty second embodiment of the present inventionprovides a pharmaceutical composition storage and administration system,wherein the mixing cup receptacle further comprises a packet portionoperable to receive up to two nightly dose packets. In some aspects, thecarton is operable to removable receive four packet containers, eachwith seven nightly dose packets, and the mixing cup receptacle with themixing cup to provide a 30-day supply of the composition.

A one hundred and eighty third embodiment of the present inventionprovides a pharmaceutical composition storage and administration system,wherein the first fill line measures about 50 mL and the second fillline measures about 25 mL.

A one hundred and eighty fourth embodiment of the present inventionprovides a pharmaceutical composition storage and administration system,wherein the mixing cup comprises a bottom and a wall having an innerside operable to intersect with the bottom. In some aspects, theintersection of the inner side of the wall and the bottom is rounded tolimit adhesion to the mixing cup. In other aspects, the intersection isnot 90 degrees.

A one hundred and eighty fifth embodiment of the present inventionprovides a method of preparing and administering a pharmaceuticalcomposition to a patient, the method comprising: providing apharmaceutical composition storage and administration system; removingthe lid of the mixing cup and filling the mixing cup with water up tothe first fill line; opening one nightly dose packet; emptying thecomposition from the nightly dose packet into the mixing cup filled withwater; replacing the lid of the mixing cup; shaking the mixing cup toform a first suspension of the composition in the water; andadministering the first suspension to the patient.

A one hundred and eighty sixth embodiment of the present inventionprovides a method of preparing and administering a pharmaceuticalcomposition to a patient, the method further comprising: removing thelid of the mixing cup and filling the mixing cup with water up to thesecond fill line; replacing the lid of the mixing cup; shaking themixing cup to form a second suspension of any residual composition inthe water; and administering the second suspension to the patient.

A one hundred and eighty seventh embodiment of the present inventionprovides a once-daily modified release formulation ofgamma-hydroxybutyrate, wherein the formulation decreases the number ofcataplexy attacks (NCA), compared to a dosing regimen consisting ofadministering the twice-nightly gamma-hydroxybutyrate treatment.

A one hundred and eighty eighth embodiment of the present inventionprovides a once-daily modified release formulation ofgamma-hydroxybutyrate, wherein the formulation produces less confusion,less depressive syndrome, less incontinence, less nausea, or lesssleepwalking, compared to a dosing regimen consisting of administeringthe twice-nightly gamma-hydroxybutyrate treatment.

A one hundred and eighty ninth embodiment of the present inventionprovides a once-daily modified release formulation ofgamma-hydroxybutyrate, wherein the formulation decreases PSG transitionsfrom N/2 to N/3 and REM sleep to wake and N1 sleep, compared to a dosingregimen consisting of administering the twice-nightlygamma-hydroxybutyrate treatment.

A one hundred and ninetieth embodiment of the present invention providesa once-daily modified release formulation of gamma-hydroxybutyrate,wherein the formulation decreases the number of arousals or wakeningsobtained from a polysomnogram, compared to a dosing regimen consistingof administering the twice-nightly gamma-hydroxybutyrate treatment.

A one hundred and ninety first embodiment of the present inventionprovides a once-daily modified release formulation ofgamma-hydroxybutyrate, wherein the formulation decreases daytimesleepiness when measured by the Maintenance of Wakefulness Test based onEEG measures of wakefulness, compared to a dosing regimen consisting ofadministering the twice-nightly gamma-hydroxybutyrate treatment.

A one hundred and ninety second embodiment of the present inventionprovides a once-daily modified release formulation ofgamma-hydroxybutyrate, wherein the formulation decreases the hypnagogichallucinations or sleep paralysis symptoms in Type 1 narcolepsypatients, compared to a dosing regimen consisting of administering thetwice-nightly gamma-hydroxybutyrate treatment.

A one hundred and ninety third embodiment of the present inventionprovides a once-daily modified release formulation ofgamma-hydroxybutyrate, wherein the formulation increases the mean sleeplatency compared to a dosing regimen consisting of administering thetwice-nightly gamma-hydroxybutyrate treatment.

A one hundred and ninety fourth embodiment of the present inventionprovides a once-daily modified release formulation ofgamma-hydroxybutyrate, wherein the formulation decreases excessivedaytime sleepiness (EDS) as measured by patient report via the EpworthSleepiness Scale (ESS), compared to a dosing regimen consisting ofadministering the twice-nightly gamma-hydroxybutyrate treatment.

A one hundred and ninety fifth embodiment of the present inventionprovides a once-daily modified release formulation ofgamma-hydroxybutyrate, wherein the formulation improves a ClinicalGlobal Impression (CGI) rating of sleepiness, compared to a dosingregimen consisting of administering the twice-nightlygamma-hydroxybutyrate treatment.

A one hundred and ninety sixth embodiment of the present inventionprovides a method of treating cataplexy or excessive daytime sleepiness(EDS) in a patient with narcolepsy by orally administering a dosage of acomposition comprising gamma-hydroxybutyrate once per night, wherein thepatient has a decrease in the number of cataplexy attacks (NCA),compared to a patient with a dosing regimen consisting of administeringthe twice-nightly gamma-hydroxybutyrate treatment.

A one hundred and ninety seventh embodiment of the present inventionprovides a method of treating cataplexy or excessive daytime sleepiness(EDS) in a patient with narcolepsy by orally administering a dosage of acomposition comprising gamma-hydroxybutyrate once per night, wherein thepatient has less confusion, less depressive syndrome, less incontinence,less nausea, or less sleepwalking, compared to a patient with a dosingregimen consisting of administering the twice-nightlygamma-hydroxybutyrate treatment.

A one hundred and ninety eighth embodiment of the present inventionprovides a method of treating cataplexy or excessive daytime sleepiness(EDS) in a patient with narcolepsy by orally administering a dosage of acomposition comprising gamma-hydroxybutyrate once per night, wherein thepatient has a decrease in PSG transitions from N/2 to N/3 and REM sleepto wake and N1 sleep, compared to a patient with a dosing regimenconsisting of administering the twice-nightly gamma-hydroxybutyratetreatment.

A one hundred and ninety ninth embodiment of the present inventionprovides a method of treating cataplexy or excessive daytime sleepiness(EDS) in a patient with narcolepsy by orally administering a dosage of acomposition comprising gamma-hydroxybutyrate once per night, wherein thepatient has a decrease in the number of arousals or wakenings obtainedfrom a polysomnogram, compared to a patient with a dosing regimenconsisting of administering the twice-nightly gamma-hydroxybutyratetreatment.

A two hundredth embodiment of the present invention provides a method oftreating cataplexy or excessive daytime sleepiness (EDS) in a patientwith narcolepsy by orally administering a dosage of a compositioncomprising gamma-hydroxybutyrate once per night, wherein the patient hasa decrease in hypnagogic hallucinations or sleep paralysis symptoms inType 1 narcolepsy patients, compared to a patient with a dosing regimenconsisting of administering the twice-nightly gamma-hydroxybutyratetreatment.

A two hundred and first embodiment of the present invention provides amethod of treating cataplexy or excessive daytime sleepiness (EDS) in apatient with narcolepsy by orally administering a dosage of acomposition comprising gamma-hydroxybutyrate once per night, wherein thepatient has a decrease in daytime sleepiness when measured by theMaintenance of Wakefulness Test based on EEG measures of wakefulness,compared to a patient administered the twice-nightlygamma-hydroxybutyrate treatment.

A two hundred and second embodiment of the present invention provides amethod of treating cataplexy or excessive daytime sleepiness (EDS) in apatient with narcolepsy by orally administering a dosage of acomposition comprising gamma-hydroxybutyrate once per night, wherein thepatient has a decrease in excessive daytime sleepiness (EDS) as measuredby patient report via the Epworth Sleepiness Scale (ESS), compared to apatient administered the twice-nightly gamma-hydroxybutyrate treatment.

A two hundred and third embodiment of the present invention provides amethod of treating cataplexy or excessive daytime sleepiness (EDS) in apatient with narcolepsy by orally administering a dosage of acomposition comprising gamma-hydroxybutyrate once per night, wherein thepatient has an increase in mean sleep latency compared to a patientadministered the twice-nightly gamma-hydroxybutyrate treatment.

A two hundred and fourth embodiment of the present invention provides amethod of treating cataplexy or excessive daytime sleepiness (EDS) in apatient with narcolepsy by orally administering a dosage of acomposition comprising gamma-hydroxybutyrate once per night, wherein thepatient improves the Clinical Global Impression-Improvement (CGI) ratingof sleepiness, compared to a patient administered the twice-nightlygamma-hydroxybutyrate treatment.

A two hundred and fifth embodiment of the present invention provides amethod of treating cataplexy or excessive daytime sleepiness (EDS) in apatient with narcolepsy comprising: orally administering a dosage of acomposition comprising 4.5-9 g of gamma-hydroxybutyrate once per night,wherein the patient experiences a plasma GHB concentration maintainedthroughout the night, and gradual decline of the GHB concentration tolowest levels by 8 to 10 hours after dosing.

A two hundred and sixth embodiment of the present invention provides amethod of treating cataplexy or excessive daytime sleepiness (EDS) in apatient with narcolepsy comprising: orally administering a dosage of acomposition comprising 4.5-9 g of gamma-hydroxybutyrate once per night,wherein the patient experiences a pharmacokinetic profile that supportsonce nightly dosing, and eliminates the need for the patient having towake up in the middle of the night to take a second dose.

A two hundred and seventh embodiment of the present invention provides amethod of treating cataplexy or excessive daytime sleepiness (EDS) in apatient with narcolepsy comprising: orally administering a dosage of acomposition comprising 4.5-9 g of gamma-hydroxybutyrate once per night,wherein the patient experiences a pharmacokinetic profile that supportsonce nightly dosing and a full 8 hours of consolidated nocturnal sleep.

A two hundred and eighth embodiment of the present invention provides amethod of treating cataplexy or excessive daytime sleepiness (EDS) in achild or adolescent patient with narcolepsy comprising: orallyadministering a dosage of a composition comprising gamma-hydroxybutyrateonce per night, wherein the child or adolescent patient dosage is notcalculated based on weight of the patient.

A two hundred and ninth embodiment of the present invention provides amethod of treating narcolepsy, cataplexy, or excessive daytimesleepiness in a human patient in need thereof, the method comprisingorally administering to the patient a once-nightly dosage ofgamma-hydroxybutyrate, wherein the patient has statistically significantimprovement on the Maintenance of Wakefulness Test (MWT) at dosages of4.5 g, 6 g, 7.5 g, and 9 g as compared to placebo.

A two hundred and tenth embodiment of the present invention provides amethod of treating narcolepsy, cataplexy, or excessive daytimesleepiness in a human patient in need thereof, the method comprisingorally administering to the patient a once-nightly dosage ofgamma-hydroxybutyrate, wherein the oral administration of theonce-nightly dosage induces the patient to fall asleep within 5 minutesof administration.

A two hundred and eleventh embodiment of the present invention providesa method of treating narcolepsy, cataplexy, or excessive daytimesleepiness in a human patient in need thereof, the method comprisingorally administering to the patient a once-nightly dosage ofgamma-hydroxybutyrate, wherein the oral administration of theonce-nightly dosage induces the patient to fall asleep within 15 minutesof administration.

A two hundred and twelfth embodiment of the present invention provides amethod of treating narcolepsy, cataplexy, or excessive daytimesleepiness in a subject comprising administering to the subject aonce-nightly dose of gamma-hydroxybutyrate, wherein 2% or fewer subjectsadministered the once-nightly dose of gamma-hydroxybutyrate experience aconfusional state.

A two hundred and thirteenth embodiment of the present inventionprovides a method of treating narcolepsy, cataplexy, or excessivedaytime sleepiness in a subject comprising administering to the subjecta once-nightly dose of gamma-hydroxybutyrate, wherein 3% or fewersubjects administered the once-nightly dose of gamma-hydroxybutyrateexperience sleepwalking.

A two hundred and thirteenth embodiment of the present inventionprovides a composition comprising an oral suspension for the treatmentof narcolepsy or excessive daytime sleepiness, the suspension comprisinga blend of granules for oral suspension in water, the granulescomprising gamma-hydroxybutyrate, wherein the oral suspension isadministered only once nightly and is effective to induce sleep in ahuman subject in need thereof for at least six hours, and wherein thecomposition provides a C_(max) which increases approximately 2-fold, andmore than dose proportionally for AUC increasing 2.3-fold, as a totaldaily dose is doubled from 4.5 g to 9 g.

A two hundred and fourteenth embodiment of the present inventionprovides a A composition of gamma-hydroxybutyrate comprising immediaterelease and modified release portions, wherein the immediate releaseportion comprises particles comprising one or more salts ofgamma-hydroxybutyrate and the modified release portion comprisesparticles comprising one or more salts of gamma-hydroxybutyrate, whereinthe particles of the modified release portion are coated with a coatingcomprising:

-   -   a. a polymer carrying free carboxylic groups, and    -   b. a hydrophobic compound having a melting point equal or        greater than 40° C.,    -   c. wherein the composition is suitable for administration only        once nightly,    -   d. wherein the composition induces sleep for at least 6        consecutive hours, and    -   e. provides a C_(max) which increases approximately 2-fold, and        more than dose proportionally for AUC increasing 2.3-fold, as a        total daily dose is doubled from 4.5 g to 9 g.

In any of these principal embodiments, the formulation is preferablyeffective to treat narcolepsy Type 1 or Type 2. The formulation is alsopreferably effective to induce sleep for six to eight, most preferablyeight consecutive hours.

In any of these principal embodiments, the formulation preferablycomprises immediate release and modified release portions, wherein themodified release portion comprises gamma hydroxybutyrate particlescoated by a polymer carrying free carboxylic groups and a hydrophobiccompound having a melting point equal or greater than 40° C., and theratio of gamma-hydroxybutyrate in the immediate release portion and themodified release portion is from 10/90 to 65/35. The polymers comprisingfree carboxylic groups preferably have a pH dissolution trigger of from5.5 to 6.97 and are preferably methacrylic acid copolymers having a pHdissolution trigger of from 5.5 to 6.97.

Principal Structural Embodiments

In a first principal structural embodiment, the invention provides amodified release formulation of gamma-hydroxybutyrate comprisingimmediate release and modified release portions, wherein: (a) themodified release portion comprises coated particles ofgamma-hydroxybutyrate; (b) the coating comprises a polymer carrying freecarboxylic groups and a hydrophobic compound having a melting pointequal or greater than 40° C.; and (c) the ratio of gamma-hydroxybutyratein the immediate release portion and the modified release portion isfrom 10/90 to 65/35.

In a second principal structural embodiment the invention provides amodified release formulation of gamma-hydroxybutyrate comprisingimmediate release and modified release portions, a suspending orviscosifying agent, and an acidifying agent, wherein: (a) the modifiedrelease portion comprises coated particles of gamma-hydroxybutyrate; (b)the coating comprises a polymer carrying free carboxylic groups and ahydrophobic compound having a melting point equal or greater than 40°C.; and (c) the ratio of gamma-hydroxybutyrate in the immediate releaseportion and the modified release portion is from 10/90 to 65/35.

In a third principal structural embodiment the invention provides amodified release formulation of gamma-hydroxybutyrate comprisingimmediate release and modified release portions, wherein: (a) themodified release portion comprises coated particles ofgamma-hydroxybutyrate; (b) the coating comprises a polymer carrying freecarboxylic groups and a hydrophobic compound having a melting pointequal or greater than 40° C.; (c) the weight ratio of the hydrophobiccompound to the polymer carrying free carboxylic groups is from 0.4 to4; (d) the ratio of gamma-hydroxybutyrate in the immediate releaseportion and the modified release portion is from 10/90 to 65/35; and (e)the coating is from 10 to 50% of the weight of the particles.

In a fourth principal structural embodiment the invention provides amodified release formulation of gamma-hydroxybutyrate comprisingimmediate release and modified release portions, wherein: (a) themodified release portion comprises coated particles ofgamma-hydroxybutyrate; (b) the coating comprises a polymer carrying freecarboxylic groups having a pH trigger of from 5.5 to 6.97 and ahydrophobic compound having a melting point equal or greater than 40°C.; (c) the weight ratio of the hydrophobic compound to the polymercarrying free carboxylic groups is from 0.4 to 4; (d) the ratio ofgamma-hydroxybutyrate in the immediate release portion and the modifiedrelease portion is from 10/90 to 65/35; and (e) the coating is from 10to 50% of the weight of the particles.

In a fifth principal structural embodiment the invention provides amodified release formulation of gamma-hydroxybutyrate comprisingimmediate release and modified release portions, wherein: (a) themodified release portion comprises coated particles ofgamma-hydroxybutyrate; (b) the coating comprises a methacrylic acidcopolymer carrying free carboxylic groups having a pH trigger of from5.5 to 6.97 and a hydrophobic compound having a melting point equal orgreater than 40° C.; (c) the weight ratio of the hydrophobic compound tothe polymer carrying free carboxylic groups is from 0.4 to 4; (d) theratio of gamma-hydroxybutyrate in the immediate release portion and themodified release portion is from 10/90 to 65/35; and (e) the coating isfrom 10 to 50% of the weight of the particles.

In an additional embodiment, a modified release formulation ofgamma-hydroxybutyrate may include immediate release and modified releaseportions, where the modified release formulation is suitable foradministration only once nightly. The formulation may be administeredonce nightly without obtundation and clinically significant respiratorydepression that occurs in adult patients treated with twice-nightlysodium oxybate. The once nightly formulation may result in reduced sideeffects of obtundation and clinically significant respiratory depressionoccurring in adult patients treated with twice-nightly sodium oxybate.In these embodiments, the immediate release portion may includegamma-hydroxybutyrate or a pharmaceutically acceptable salt thereof, andthe modified release portion may include gamma-hydroxybutyrate or apharmaceutically acceptable salt thereof coated with a coatingcomprising: a polymer carrying free carboxylic groups, and a hydrophobiccompound having a melting point equal or greater than 40° C.

Discussion of Pharmacokinetic and Dissolution Sub-Embodiments

As mentioned in the definitions section of this document, each of thesub-embodiments may be used to further characterize and limit each ofthe foregoing principal embodiments. In addition, more than one of thefollowing sub-embodiments may be combined and used to furthercharacterize and limit each of the foregoing principal embodiments, inany manner that is mathematically and physically possible.

In some sub-embodiments, the formulation yields a plasma concentrationversus time curve when administered at a dose of 4.5 g, 6.0 g or 7.5 gapproximately two hours after a standardized evening meal substantiallyas depicted in FIG. 12 or FIG. 13 for the corresponding dose.

In additional sub-embodiments, the formulation yields a plasmaconcentration versus time curve when administered at a dose of 4.5 gapproximately two hours after a standardized evening meal substantiallyas depicted in FIG. 22 .

In other sub-embodiments, the formulation yields a dissolution profilesubstantially as depicted in FIG. 7 , FIG. 8 , FIG. 20 , FIG. 21 ,and/or FIGS. 29 through 89 . The formulation may yield a dissolutionprofile between the minimum and maximum values depicted in FIG. 25 ,FIG. 26 , FIG. 27 , and/or FIG. 28 .

In some sub-embodiments, the modified release portion yields adissolution profile substantially as depicted in FIG. 3 or FIG. 16 .

In additional sub-embodiments, the formulation yields a plasmaconcentration versus time curve when administered at a dose of 4.5 g,7.5 g or 9.0 g approximately two hours after a standardized evening mealsubstantially as depicted in FIG. 90 for the corresponding dose.

In other sub-embodiments, the formulation produces a residual drugcontent in the bloodstream similar to one observed after administrationof an equal dose of an immediate release liquid solution of sodiumoxybate administered twice nightly.

In various sub-embodiments of the foregoing principal embodiments a 7.5g dose of the modified release formulation of gamma-hydroxybutyrate maybe characterized as having been shown to achieve a mean AUC_(inf) ofgreater than 245, 265, 285, 300, 315, 325, 340, 350, 375, 400, 425, or450 hr×microgram/mL when administered once approximately two hours aftera standardized evening meal. An upper limit on mean AUC_(inf) for such7.5 g dose may be set at 500 or 550 hr×microgram/mL.

In additional sub-embodiments of the foregoing principal embodiments a7.5 g dose of the modified release formulation of gamma-hydroxybutyratemay be characterized as having been shown to achieve a mean C_(max) ofgreater than 65, 70, 75, 80, 85, or 90 microgram/mL when administeredonce approximately two hours after a standardized evening meal. An upperlimit on mean Cm, for such 7.5 g dose may be set at 125 or 100microgram/mL. In other embodiments, a 6 g dose of the modified releaseformulation of gamma-hydroxybutyrate may be characterized as having beenshown to achieve a mean C_(max) of greater than 50, 55, 60, 65, 70, 75,or 80 microgram (mcg)/mL when administered once nightly. In at least oneembodiment, following oral administration of the formulation ofgamma-hydroxybutyrate, the C_(max) of a 6 g dose may be about 65.8mcg/mL.

In additional sub-embodiments of the forgoing principal embodiments a7.5 g dose of the modified release formulation of gamma-hydroxybutyratemay be characterized as having been shown to achieve a mean C_(8h) thatis from 50% to 130%, from 60% to 130%, from 70 to 130%, from 75% to125%, from 80% to 125%, from 80 to 120%, or from 90% to 110% of the meanC_(8h) provided by an equal dose of immediate release liquid solution ofgamma-hydroxybutyrate administered at t₀ and t_(4h) in two equallydivided doses, when administered approximately two hours after astandardized evening meal.

In one sub-embodiment, a 7.5 g dose of the formulation has been shown toachieve a mean AUC_(inf) of greater than 340 hr·microgram/mL, and a meanC_(8h) that is from 50% to 130% of the mean C_(8h) provided by an equaldose of immediate release liquid solution of sodium oxybate administeredat t₀ and t_(4h) in equally divided doses approximately two hours aftera standardized evening meal.

Further sub-embodiments may be characterized based on the dissolutionproperties of the entire (or finished) modified release formulation ofgamma-hydroxybutyrate in 0.1N hydrochloric acid dissolution medium.Thus, in additional sub-embodiments the entire modified releaseformulation of gamma-hydroxybutyrate releases greater than 30%, 35%,40%, or 45%, and less than 70%, 65%, 60%, or 55%, of itsgamma-hydroxybutyrate at one hour when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm.

Further sub-embodiments may be defined based on the dissolutionproperties of the modified release portion of the formulation ofgamma-hydroxybutyrate in a phosphate buffer pH 6.8 dissolution medium.Thus, in additional sub-embodiments the modified release portionreleases greater than 80%, 85%, 90%, 95%, 98% or even 99% of itsgamma-hydroxybutyrate at 3, 2, 1, 0.5 or 0.25 hours when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.05Mmonobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C.and a paddle speed of 75 rpm.

Still further embodiments may be defined based on the dissolutionproperties of the modified release portion of the modified releaseformulation of gamma-hydroxybutyrate in a 0.1N HCl dissolution medium.Thus, in additional sub-embodiments the modified release portionreleases less than 20%, 15%, 10%, 5%, or even 2% of itsgamma-hydroxybutyrate at one hour when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm.

In additional embodiments, the modified release portion releases lessthan 20%, 15%, 10%, 5%, or even 2% of its gamma-hydroxybutyrate at onehour and at three hours and more than 30%, 35%, 40%, 45% of itsgamma-hydroxybutyrate at ten hours when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.1N hydrochloricacid at a temperature of 37° C. and a paddle speed of 75 rpm.

Further embodiments may be defined based on the dissolution propertiesof the immediate release portion of the modified release formulation ofgamma-hydroxybutyrate in a 0.1N HCl dissolution medium. Thus, inadditional sub-embodiments the immediate release portion releasesgreater than 80%, 85%, 90%, 95%, 98% or even 99% of itsgamma-hydroxybutyrate at one hour when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm.

In another sub-embodiment, the formulation releases (a) at least 80% ofits gamma-hydroxybutyrate at three hours when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasicpotassium phosphate buffer pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm, and (b) from 10% to 65%, of itsgamma-hydroxybutyrate at one hour and three hours when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm.

In another sub-embodiment, the formulation comprises immediate releaseand modified release portions, and (a) the formulation releases at least80% of its gamma-hydroxybutyrate at 3 hours when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasicpotassium phosphate buffer pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm, (b) the formulation releases from 10% to 65%, ofits gamma-hydroxybutyrate at one hour when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.1N hydrochloricacid at a temperature of 37° C. and a paddle speed of 75 rpm, and (c)the modified release portion releases greater than 80% of itsgamma-hydroxybutyrate at 3 hours in a dissolution test started in 750 mLof 0.1N hydrochloric acid for 2 hours then switched to 950 mL 0.05Mmonobasic potassium phosphate buffer adjusted to pH 6.8 at a temperatureof 37° C. and a paddle speed of 75 rpm.

In another sub-embodiment, the formulation comprises immediate releaseand modified release portions, and (a) the formulation releases at least80% of its gamma-hydroxybutyrate at 3 hours when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasicpotassium phosphate buffer pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm, (b) the formulation releases 10% to 65% of itsgamma-hydroxybutyrate at one hour and at three hours when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm, (c) the formulation releases greater than 60% of itsgamma-hydroxybutyrate at 10 hours when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm, and (d) the modifiedrelease portion releases greater than 80% of its gamma-hydroxybutyrateat 3 hours in a dissolution test started in 750 mL of 0.1N hydrochloricacid for 2 hours then switched to 950 mL 0.05M monobasic potassiumphosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm.

Still further sub-embodiments may be defined based on a pharmacokineticcomparison of the modified release formulation of gamma-hydroxybutyrateto an immediate release solution of gamma-hydroxybutyrate. Therefore, inadditional sub-embodiments the modified release formulation ofgamma-hydroxybutyrate, preferably in a 4.5 g, 6.0 g, 7.5 g, and 9.0 gdose, has been shown to achieve a relative bioavailability (RBA) ofgreater than 80%, 85%, 90%, or 95% when compared to an equal dose of animmediate release liquid solution of sodium oxybate administered at t₀and t_(4h) in equally divided doses, when administered approximately twohours after a standardized evening meal.

In additional sub-embodiments of the forgoing principal embodiments theinvention provides a modified release formulation ofgamma-hydroxybutyrate, preferably comprising immediate release andmodified release portions, wherein a 4.5 g and 9 g dose of theformulation has been shown to achieve a relative bioavailability (RBA)of greater than 80%, 85% or 90% when compared to an equal dose of animmediate release liquid solution of sodium oxybate administered at t₀and t_(4h) in equally divided doses, when administered approximately twohours after a standardized evening meal

In additional sub-embodiments, a 6.0 g or 7.5 g or 9.0 g dose of themodified release formulation of gamma-hydroxybutyrate has been shown toachieve a relative bioavailability (RBA) of greater than 80%, 85%, 90%,95% or 100% when compared to an equal dose of an immediate releaseliquid solution of sodium oxybate administered at t₀ and t_(4h) inequally divided doses, when administered approximately two hours after astandardized evening meal. In an example, a 4.5 g, 6.0 g, 7.5 g or 9.0 gdose of the modified release formulation of gamma-hydroxybutyrate hasbeen shown to achieve an absolute bioavailability of about 88%.

The modified release formulations of gamma-hydroxybutyrate of thepresent invention may also be defined by comparing the area under theconcentration/time curve for eight hours to the area under theconcentration/time curve calculated to infinity. Thus, in still furthersub-embodiments a 4.5 g, 6.0 g, 7.5 g or 9.0 g dose of the modifiedrelease formulation of gamma-hydroxybutyrate of the present inventionhas been shown to achieve a ratio of AUC_(8h) to AUC_(inf) of greaterthan 0.80, 0.85, 0.90, 0.95 or 0.98 when administered once approximatelytwo hours after a standardized evening meal.

In still further sub-embodiments, the modified release formulations ofgamma-hydroxybutyrate are defined based on the concentration ofgamma-hydroxybutyrate in the blood stream 8 hours after administration.Therefore, in other sub-embodiments the formulation may be characterizedby a 4.5 g dose of the modified release formulation ofgamma-hydroxybutyrate that has been shown to achieve a mean C_(8h) offrom 3.5 to 4.7, 4.7 to 9.0, from 5.4 to 8.3, from 6.1 to 7.6, from 3.5to 7.0, or from 4.0 to 5.5 microgram/mL, a 6.0 g dose of the modifiedrelease formulation of gamma-hydroxybutyrate has been shown to achieve amean C_(8h) of from 6.3 to 16.7, from 7.3 to 15.4, from 8.2 to 14.1,from 8.9 to 16.7, from 10.2 to 15.4, or from 11.5 to 14.1 microgram/mL;or a 7.5 g dose of the modified release formulation ofgamma-hydroxybutyrate has been shown to achieve a mean C_(8h) of from13.0 to 40.3, from 16.0 to 26.0, 15.0 to 25.0, from 17.5 to 22.0, from21.6 to 40.3, from 24.7 to 37.2, or from 27.8 to 34.1 microgram/mL, whenadministered once approximately two hours after a standardized eveningmeal.

The modified release formulations of gamma-hydroxybutyrate of thepresent invention may also be defined by the concentration/time anddissolution curves that they produce when tested according to theexamples of the present invention. Therefore, in other sub-embodiments,a 4.5 g, 6.0 g, or 7.5 g dose of the modified release formulation ofgamma-hydroxybutyrate of the present invention has been shown to achievea time/concentration curve substantially as shown in FIGS. 13 (a), (b)and (c) respectively herein. In another principal embodiment orsub-embodiment, the formulation has been shown to achieve a dissolutioncurve substantially as shown in FIGS. 7 and 8 or FIGS. 20 and 21 herein.

The modified release formulations of gamma-hydroxybutyrate of thepresent invention may also be defined based on the time required toreach maximum blood concentration of gamma-hydroxybutyrate. Thus, inadditional sub-embodiments, the modified release formulation ofgamma-hydroxybutyrate has been shown to achieve a median T_(max) of 0.5to 3.25 hours or 1.25 to 3.25 hours, preferably of about 1.25, 1.5,1.75, 2, 2.25, 2.5, 2.75, 3, or 3.25 hours when administered onceapproximately two hours after a standardized evening meal. A lower limiton the median T_(max) in any of the foregoing ranges may alternativelybe set at 0.5 or 1.0 hours. In at least one example, the T_(max) of theformulation is about 1.5 hours.

Additional embodiments may be defined by comparing a dose of themodified release formulation of gamma-hydroxybutyrate, administered oncenightly, to the same dose of an immediate release liquid solution ofsodium oxybate divided in half and administered twice nightly, 4 hoursapart. Thus, in another sub-embodiment a 4.5 g, 6.0 g, 7.5 g or 9.0 gdose of the modified release formulation of gamma-hydroxybutyrate hasbeen shown to achieve a median T_(max) within one hundred fifty, onehundred twenty, ninety, sixty or thirty minutes of the median T_(max) ofhalf the dose of an immediate release liquid solution of sodium oxybate,when administered approximately two hours after a standardized eveningmeal.

In still another sub-embodiment a 4.5 g, 6.0 g, 7.5 g or 9.0 g dose ofthe modified release formulation of gamma-hydroxybutyrate has been shownto achieve a mean C_(6h) or mean C_(7h) greater than, and a mean C_(10h)less than, the mean C_(4h) of half the dose of an immediate releaseliquid solution of sodium oxybate, when administered approximately twohours after a standardized evening meal.

Additional embodiments may be defined by comparing the pharmacokineticprofile of a dose of the modified release formulation ofgamma-hydroxybutyrate administered once nightly to the same dose of animmediate release liquid solution of sodium oxybate divided in half andadministered twice nightly, 4 hours apart. Thus, in anothersub-embodiment a modified release formulation of gamma-hydroxybutyrateaccording to the invention has been shown to achieve a ratio of its meanC₃ h to the mean C_(max) of the first half dose of the immediate releaseliquid solution of sodium oxybate from 0.6 to 1.2, preferably from 0.7to 1.1 and most preferably from 0.8 to 1. In another sub-embodiment, amodified release formulation of gamma-hydroxybutyrate according to theinvention has been shown to achieve a ratio of its mean C_(4h) to themean C_(max) of the first half dose of the immediate release liquidsolution of sodium oxybate from 0.5 to 1.1, preferably from 0.6 to 1 andmost preferably from 0.7 to 0.9. In another sub-embodiment, a modifiedrelease formulation of gamma-hydroxybutyrate according to the inventionhas been shown to achieve a ratio of its mean C_(4.5h) to the meanC_(max) of the first half dose of the immediate release liquid solutionof gamma-hydroxybutyrate from 0.5 to 1, preferably from 0.5 to 0.9 andmost preferably from 0.6 to 0.8.

Additional sub-embodiments may be defined by the range of mean bloodconcentrations of gamma-hydroxybutyrate achieved 3, 4, 4.5 or 5 hoursafter administration once nightly by a modified release formulation ofgamma-hydroxybutyrate according to the invention at the dose of 7.5 g.Thus, in another sub-embodiment, a 7.5 g dose of the modified releaseformulation of gamma-hydroxybutyrate has been shown to achieve a meanC_(3h) of 43 to 81 microgram/mL, preferably 49 to 75 microgram/mL andmore preferably 55 to 69 microgram/mL. In another sub-embodiment, a 7.5g dose of the modified release formulation of gamma-hydroxybutyrate hasbeen shown to achieve a mean C₄ h of 40 to 75 microgram/mL, preferably45 to 69 microgram/mL and more preferably 51 to 64 microgram/mL. Inanother sub-embodiment, a 7.5 g dose of the modified release formulationof gamma-hydroxybutyrate has been shown to achieve a mean C_(4.5h) of 35to 67 microgram/mL, preferably 40 to 62 microgram/mL and more preferably45 to 56 microgram/mL. In another sub-embodiment, a 7.5 g dose of themodified release formulation of gamma-hydroxybutyrate has been shown toachieve a mean C_(5h) of 31 to 59 microgram/mL, preferably 36 to 55microgram/mL and more preferably 40 to 50 microgram/mL.

In another sub-embodiment, a 7.5 g dose of the formulation has beenshown to achieve a mean AUC_(inf) of greater than 300 hr·microgram/mLand a mean Cmax of greater than 70 microgram/mL when administered onceapproximately two hours after a standardized evening meal.

In still another sub-embodiment, a 7.5 g dose of the formulation hasbeen shown to achieve a mean AUC_(inf) of greater than 350hr·microgram/mL and a mean C_(max) of greater than 80 microgram/mL whenadministered once approximately two hours after a standardized eveningmeal.

In another sub-embodiment, a 4.5, 6.0, 7.5 and 9.0 g dose of theformulation has been shown to achieve a mean AUC_(inf) of greater than80% of the mean AUC_(inf) provided by an equal dose of immediate releaseliquid solution of sodium oxybate administered at t₀ and t_(4h) inequally divided doses approximately two hours after a standardizedevening meal, and a mean C_(8h) less than 95%, 90 or 85% of the meanC_(8h) provided by an equal dose of immediate release liquid solution ofsodium oxybate administered at t₀ and t_(4h) in equally divided dosesapproximately two hours after a standardized evening meal.

Additional embodiments may be defined by comparing the pharmacokineticprofile of a dose of the modified release formulation ofgamma-hydroxybutyrate administered once nightly to another dose of animmediate release liquid solution of sodium oxybate divided in half andadministered twice nightly, 4 hours apart. Thus, in anothersub-embodiment a 7.5 g dose of the modified release formulation ofgamma-hydroxybutyrate has been shown to achieve a similarpharmacokinetic profile to the pharmacokinetic profile provided by a2×4.5 g dose of sodium oxybate as an immediate release liquid solutionadministered for the first 4.5 g two hours after a standardized eveningmeal and for the second 4.5 g dose, 4 hours after the first dose. Thus,in another sub-embodiment a modified release formulation ofgamma-hydroxybutyrate according to the invention administered at thedose of 7.5 g has been shown to achieve a ratio of its mean C_(3h) tothe mean C_(max) of the first 4.5 g dose of the immediate release liquidsolution of sodium oxybate from 0.5 to 1.1, preferably from 0.6 to 1 andmost preferably from 0.7 to 0.9. In another sub-embodiment, a modifiedrelease formulation of gamma-hydroxybutyrate according to the inventionhas been shown to achieve a ratio of its mean C₄ h to the mean C_(max)of the first 4.5 g dose of the immediate release liquid solution ofsodium oxybate from 0.5 to 1, preferably from 0.6 to 0.9 and mostpreferably from 0.7 to 0.8. In another sub-embodiment, a modifiedrelease formulation of gamma-hydroxybutyrate according to the inventionhas been shown to achieve a ratio of its mean C4.5 h to the mean C_(max)of the 4.5 g dose of the immediate release liquid solution of sodiumoxybate from 0.4 to 0.9, preferably from 0.5 to 0.8 and most preferablyfrom 0.6 to 0.7.

The modified release formulation of gamma-hydroxybutyrate administeredonce nightly at 4.5 and 6 g may have lower overall Cmax and C_(8h) andsimilar exposure and variability compared with twice-nightly sodiumoxybate. In an embodiment, the modified release formulation ofgamma-hydroxybutyrate administered once nightly may have a lowerC_(max), lower plasma concentration 8 h after dosing (C_(8h)), similarexposure (AUC), and comparable interperson variability to twice-nightlysodium oxybate 4.5 g. In some embodiments, there may be a similar sleepquality and morning alertness between the modified release formulationof gamma-hydroxybutyrate administered once nightly and twice-nightlysodium oxybate. In an embodiment, the modified release formulation ofgamma-hydroxybutyrate administered once nightly may have doseproportionality for C_(max) and about dose proportionality for AUC. A 6g dose of the modified release formulation of gamma-hydroxybutyrateadministered once nightly may have a lower C_(max) and C_(8h) thantwice-nightly sodium oxybate at 6 g but equivalent AUC and comparablevariability. In some embodiments, a 6 g dose of the modified releaseformulation of gamma-hydroxybutyrate administered once nightly may havea longer T_(max) (1 h later), lower C_(max) (67%), and decreased AUC(86%) in fed versus fasted states. Adverse events with the modifiedrelease formulation of gamma-hydroxybutyrate administered once nightlymay be mostly mild or moderate in severity, nonserious, and known to beassociated with sodium oxybate. Safety profiles of the modified releaseformulation of gamma-hydroxybutyrate administered once nightly andtwice-nightly sodium oxybate at 4.5 and 6 g may be similar.

In direct comparison to twice-nightly sodium oxybate, the modifiedrelease formulation of gamma-hydroxybutyrate administered once nightlymay have bioequivalent exposure at the 4.5- and 6 g doses. Indirectcomparison to twice-nightly sodium oxybate from the published literaturesuggests that the modified release formulation of gamma-hydroxybutyrateadministered once nightly may have a more predictable pharmacokineticprofile with ascending doses (dose-proportional increase in C_(max) andslightly more than dose-proportional increase in AUC_(inf) [e.g. anapproximate 2.3-fold increase in plasma GHB concentration with a 2-folddose increase]). Twice-nightly sodium oxybate treatment produces a3.7-fold increase in plasma GHB concentration with a 2-fold doseincrease, indicating nonlinear clearance and necessitating weight-baseddosing in pediatric populations. Moreover, the pharmacokinetic profileof the modified release formulation of gamma-hydroxybutyrateadministered once nightly suggests that food may have less of an effecton GHB concentrations, particularly overall exposure, than twice-nightlysodium oxybate. In twice-nightly sodium oxybate, significant differenceswere observed for T_(max), C_(max), and AUC_(inf), with C_(max)values >2-fold higher in the fasted versus fed states. This differencewas reflected by second-dose T_(max) and C_(max) (relatively fastedstate at 6 h after eating) being higher than first-dose T_(max) andC_(max) (relatively fed state at 2 h after eating) with twice-nightlySO. The increase in Cmax observed with the second dose of twice-nightlysodium oxybate (i.e., the relatively fasted state) and associatedadverse events could potentially lead some patients to eat during thenight before taking their second dose to avoid adverse events associatedwith high C_(max) further disrupting nocturnal sleep.

The modified release formulation of gamma-hydroxybutyrate administeredonce nightly eliminates the risks associated with having to wake up inthe middle of the night to take the second dose. The modified releaseformulation of gamma-hydroxybutyrate administered once nightly may alsooffer other clinical benefits over twice-nightly sodium oxybate inpatients with narcolepsy. Once-nightly dosing in itself may have apositive effect on disrupted nocturnal sleep, allowing a full 8 hours ofconsolidated nocturnal sleep.

A temporal relationship has been observed between incidence of adverseevents and C_(max) with twice-nightly sodium oxybate. The single C_(max)with the modified release formulation of gamma-hydroxybutyrateadministered once nightly is lower than those of twice-nightly sodiumoxybate, which may translate into fewer C_(max)-associated adverseevents. In some embodiments, 8-hour GHB levels with the modified releaseformulation of gamma-hydroxybutyrate administered once nightly may beslightly lower than with twice-nightly sodium oxybate, and there may beno observable difference between the modified release formulation ofgamma-hydroxybutyrate administered once nightly and twice-nightly sodiumoxybate in the “awake following sleep” domain of the LSEQ. In anembodiment, the modified release formulation of gamma-hydroxybutyrateadministered once nightly may produce dose proportionality in the GHBconcentration. This predictable dosing profile may avoid theweight-based dosing currently needed in children and adolescents treatedwith twice-nightly sodium oxybate. Pharmacokinetic parameters of themodified release formulation of gamma-hydroxybutyrate administered oncenightly may be affected to a lesser extent in relation to food intakecompared with those of twice-nightly sodium oxybate. Thus, the modifiedrelease formulation of gamma-hydroxybutyrate administered once nightlymay also be administered with food or less than 2 hours after eating.

In another sub-embodiment, the modified release formulation ofgamma-hydroxybutyrate comprises immediate release and modified releaseportions, wherein: (a) said immediate release portion releases greaterthan 80% of its gamma-hydroxybutyrate at one hour when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm; (b) said modified release portion releases less than 20% of itsgamma-hydroxybutyrate at one hour when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm; and (c) saidmodified release portion releases greater than 80% of itsgamma-hydroxybutyrate at one hour when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.05M monobasic potassiumphosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of75 rpm.

In a preferred embodiment, the modified release formulation ofgamma-hydroxybutyrate according to the invention achieves an in vitrodissolution profile:

-   -   (a) measured in a dissolution apparatus 2 according to USP 38        <711> in 900 mL of 0.1N hydrochloric acid at a temperature of        37° C. and a paddle speed of 75 rpm, characterized by the        percentage of gamma-hydroxybutyrate dissolved being:        -   (i) from 40% to 65% at 1 hour,        -   (ii) from 40% to 65% at 3 hours,        -   (iii) from 47% to 85% at 8 hours,        -   (iv) greater or equal to 60% at 10 hours,        -   (v) greater or equal to 80% at 16 hours, and    -   (b) measured in a dissolution apparatus 2 according to USP 38        <711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH        6.8 at a temperature of 37° C. and a paddle speed of 75 rpm,        characterized by the percentage of gamma-hydroxybutyrate        dissolved being:        -   (i) from 43% to 94% at 0.25 hour,        -   (ii) greater or equal to 65% at 0.35 hour, and        -   (iii) greater or equal to 88% at 1 hour.

In a preferred embodiment, the modified release formulation ofgamma-hydroxybutyrate according to the invention achieves an in vitrodissolution profile:

-   -   (a) measured in a dissolution apparatus 2 according to USP 38        <711> in 900 mL of 0.1N hydrochloric acid at a temperature of        37° C. and a paddle speed of 75 rpm, characterized by the        percentage of gamma-hydroxybutyrate dissolved being:        -   (i) from 40% to 65% at 1 hour,        -   (ii) from 40% to 65% at 3 hours,        -   (iii) greater or equal to 47% at 8 hours,        -   (iv) greater or equal to 60% at 10 hours,        -   (v) greater or equal to 80% at 16 hours, and    -   (b) measured in a dissolution apparatus 2 according to USP 38        <711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH        6.8 at a temperature of 37° C. and a paddle speed of 75 rpm,        characterized by the percentage of gamma-hydroxybutyrate        dissolved being:        -   (i) from 43% to 94% at 0.25 hour,        -   (ii) greater or equal to 65% at 0.35 hour, and        -   (iii) greater or equal to 88% at 1 hour.

In another preferred embodiment, the modified release formulation ofgamma-hydroxybutyrate according to the invention achieves an in vitrodissolution profile:

-   -   (a) measured in a dissolution apparatus 2 according to USP 38        <711> in 900 mL of 0.1N hydrochloric acid at a temperature of        37° C. and a paddle speed of 75 rpm, characterized by the        percentage of gamma-hydroxybutyrate dissolved being:        -   (i) from 40% to 65% at 1 hour,        -   (ii) from 40% to 65% at 3 hours,        -   (iii) from 47% to 85% at 8 hours,        -   (iv) greater or equal to 60% at 10 hours,        -   (v) greater or equal to 80% at 16 hours, and    -   (b) measured in a dissolution apparatus 2 according to USP 38        <711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH        6.8 at a temperature of 37° C. and a paddle speed of 75 rpm,        characterized by the percentage of gamma-hydroxybutyrate        dissolved being:        -   (i) from 45% to 67% at 1 hour, and        -   (ii) greater or equal to 65% at 3 hours.

In another preferred embodiment, the modified release formulation ofgamma-hydroxybutyrate according to the invention achieves an in vitrodissolution profile:

-   -   (a) measured in a dissolution apparatus 2 according to USP 38        <711> in 900 mL of 0.1N hydrochloric acid at a temperature of        37° C. and a paddle speed of 75 rpm, characterized by the        percentage of gamma-hydroxybutyrate dissolved being:        -   (i) from 40% to 65% at 1 hour,        -   (ii) from 40% to 65% at 3 hours,        -   (iii) greater or equal to 47% at 8 hours,        -   (iv) greater or equal to 60% at 10 hours,        -   (v) greater or equal to 80% at 16 hours, and    -   (b) measured in a dissolution apparatus 2 according to USP 38        <711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH        6.8 at a temperature of 37° C. and a paddle speed of 75 rpm,        characterized by the percentage of gamma-hydroxybutyrate        dissolved being:        -   (i) from 45% to 67% at 1 hour, and        -   (ii) greater or equal to 65% at 3 hours.

In still another sub-embodiment, the formulation achieves an in vitrodissolution profile: (a) measured in a dissolution apparatus 2 accordingto USP 38 <711> in 900 mL of 0.1N hydrochloric acid at a temperature of37° C. and a paddle speed of 75 rpm, characterized by the percentage ofgamma-hydroxybutyrate dissolved being: (i) from 40% to 65% at 1 hour,(ii) from 40% to 65% at 3 hours, (iii) greater than 45% at 8 hours, and(b) measured in a dissolution apparatus 2 according to USP 38 <711> in900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at atemperature of 37° C. and a paddle speed of 75 rpm, characterized by thepercentage of gamma-hydroxybutyrate dissolved being: (i) greater than40% at 0.5 hour, and (ii) greater than 85% at 1 hour.

Alternatively, the formulation may be described as achieving an in vitrodissolution profile measured in a dissolution apparatus 2 according toUSP 38 <711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37°C. and a paddle speed of 75 rpm, characterized by the percentage ofgamma-hydroxybutyrate dissolved being: (i) from 40% to 65% at 1 hour,(ii) from 40% to 65% at 3 hours, and (iii) greater than 45% at 8 hours.

In another alternative, the formulation may be described as achieving anin vitro dissolution profile measured in a dissolution apparatus 2according to USP 38 <711> in 900 mL of 0.05M monobasic potassiumphosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of75 rpm, characterized by the percentage of gamma-hydroxybutyratedissolved being: (i) greater than 40% at 0.5 hour, and (ii) greater than85% at 1 hour.

In some embodiments, the formulation is resistant to alcohol-induceddose dumping. For example, ethanol concentrations from about 5% to about20% may not change the dissolution profile of the formulation. Inadditional embodiments, the modified release portion provides a modifiedrelease profile, and the release rate when measured using a first invitro dissolution test in the absence of ethanol and the release ratewhen using a second vitro dissolution test in the presence of about 5%to about 20% ethanol (v/v) are substantially the same, where, other thanthe absence or presence ethanol, the first in vitro dissolution test andthe second in vitro dissolution test are the same.

Structural Sub-Embodiments

The modified release formulations of gamma-hydroxybutyrate of thepresent invention may be provided in any dosage form that is suitablefor oral administration, including tablets, capsules, liquids, orallydissolving tablets, and the like, but they are preferably provided asdry particulate formulations (i.e. granules, powders, coated particles,microparticles, pellets, microspheres, etc.), in a sachet or othersuitable discreet packaging units. A preferred particulate formulationwill be mixed with tap water shortly before administration, preferably30-50 mL. In some embodiments, the formulation is a dry particulateformulation or a powdered formulation. In various embodiments, theformulation is suitable for oral administration once daily, for example,once nightly.

In various embodiments, the formulation may include a pharmaceuticallyacceptable salt of gamma-hydroxybutyrate selected from a sodium salt ofgamma-hydroxybutyric acid, a calcium salt of gamma-hydroxybutyric acid,a potassium salt of gamma-hydroxybutyric acid, and/or a magnesium saltof gamma-hydroxybutyric acid. In some examples, the pharmaceuticallyacceptable salt of gamma-hydroxybutyrate is a calcium salt ofgamma-hydroxybutyric acid.

In one sub-embodiment, the formulation comprises immediate release andmodified release portions, wherein: (a) the modified release portioncomprises coated microparticles of gamma-hydroxybutyrate; and (b) theratio of gamma-hydroxybutyrate in the immediate release portion and themodified release portion is from 10/90 to 65/35.

In one sub-embodiment, the formulation comprises immediate release andmodified release portions, wherein: (a) the modified release portioncomprises coated microparticles of gamma-hydroxybutyrate; and (b) theratio of gamma-hydroxybutyrate in the immediate release portion and themodified release portion is from 40/60 to 60/40.

In another sub-embodiment, the formulation comprises immediate releaseand modified release portions, wherein: (a) the modified release portioncomprises coated microparticles of gamma-hydroxybutyrate; (b) thecoating of said modified release particles of gamma-hydroxybutyratecomprises a polymer carrying free carboxylic groups and a hydrophobiccompound having a melting point equal or greater than 40° C.; and (c)the ratio of gamma-hydroxybutyrate in the immediate release portion andthe modified release portion is from 10/90 to 65/35 or 40/60 to 60/40.

In another sub-embodiment, the formulation comprises immediate releaseand modified release portions, wherein: (a) the modified release portioncomprises coated microparticles of gamma-hydroxybutyrate; (b) thecoating of said modified release particles of gamma-hydroxybutyratecomprises a polymer carrying free carboxylic groups and a hydrophobiccompound having a melting point equal or greater than 40° C.; (c) theweight ratio of the hydrophobic compound to the polymer carrying freecarboxylic groups is from 0.4 to 4; (d) the ratio ofgamma-hydroxybutyrate in the immediate release portion and the modifiedrelease portion is from 10/90 to 65/35 or 40/60 to 60/40; and (e) thefilm coating is from 10 to 50% of the weight of the microparticles.

In another sub-embodiment the formulation comprises immediate releaseand modified release portions, wherein: (a) the modified release portioncomprises coated particles of gamma-hydroxybutyrate; (b) the coating ofsaid modified release particles of gamma-hydroxybutyrate comprises apolymer carrying free carboxylic groups having a pH trigger of from 5.5to 6.97 and a hydrophobic compound having a melting point equal orgreater than 40° C.; (c) the weight ratio of the hydrophobic compound tothe polymer carrying free carboxylic groups is from 0.4 to 4; (d) theratio of gamma-hydroxybutyrate in the immediate release portion and themodified release portion is from 10/90 to 65/35 or 40/60 to 60/40; and(e) the coating is from 10 to 50% of the weight of the particles.

In some embodiments, the formulation comprises a modified releaseportion comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate and at least one coating on thegamma-hydroxybutyrate, where the coating comprises a polymer carryingfree carboxylic groups and a hydrophobic compound having a melting pointequal or greater than 40° C. The weight ratio of the hydrophobiccompound to the polymer carrying free carboxylic groups may be from 0.4to 4.

In other embodiments, the formulation may further comprisemicrocrystalline cellulose. The microcrystalline cellulose may bepresent at about 10% w/w-15% w/w. In additional embodiments, theformulation may further include a layer of hydroxypropyl cellulose.

In some embodiments, the polymer carrying free carboxylic groups in thecoating may have a pH-dependent solubility. In various embodiments, thepolymer carrying free carboxylic groups is selected from (meth)acrylicacid/alkyl (meth)acrylate copolymers, methacrylic acid andmethylmethacrylate copolymers, methacrylic acid and ethyl acrylatecopolymers, methacrylic acid copolymers type A, B or C, cellulosederivatives carrying free carboxylic groups, preferably celluloseacetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, carboxymethylethyl cellulose, cellulose acetatetrimellitate, hydroxypropyl methyl cellulose acetate succinate,polyvinyl acetate phthalate, zein, shellac, alginate, and mixturesthereof.

In additional embodiments, the polymer carrying free carboxylic groupscomprises a methacrylic acid copolymer. Non-limiting examples of themethacrylic acid copolymer include poly (methacrylic acid, methylmethacrylate) 1:1, poly (methacrylic acid, ethyl acrylate) 1:1, poly(methacrylic acid, methyl methacrylate) 1:2, and mixtures thereof. Inadditional aspects, the methacrylic acid copolymer comprisespoly(methacrylic acid, ethyl acrylate) 1:1.

In some sub-embodiments, the polymer carrying free carboxylic groupscomprises from 100% poly (methacrylic acid, ethyl acrylate) 1:1 and 0%poly (methacrylic acid, methylmethacrylate) 1:2 to 2% poly (methacrylicacid, ethyl acrylate) 1:1 and 98% poly (methacrylic acid,methylmethacrylate) 1:2; and the hydrophobic compound compriseshydrogenated vegetable oil.

In an embodiment, the coating comprises from 10 to 50%, 10 to 20%, 20 to30%, 30 to 40%, or 40 to 50% of the weight of the modified releaseportion.

In some embodiments, the formulation may further include an immediaterelease portion comprising a pharmaceutically acceptable salt ofgamma-hydroxybutyrate. In an embodiment, the formulation furthercomprises xanthan gum, carrageenan gum, gellan gum, guar gum, sodiumalginate, calcium alginate, agar, sodium carboxymethyl cellulose,microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, or mixtures thereof. In at least one example, the formulationcomprises guar gum. For example, the guar gum may be present at 1% to15% by weight of the formulation.

In a preferred embodiment, the formulation includes excipients toimprove the viscosity and the pourability of the mixture of theparticulate formulation with tap water. As such, the particulateformulation comprises, besides the immediate release and modifiedrelease particles of gamma-hydroxybutyrate, one or more suspending orviscosifying agents or lubricants.

Preferred suspending or viscosifying agents are chosen from the groupconsisting of xanthan gum, medium viscosity sodium carboxymethylcellulose, mixtures of microcrystalline cellulose and sodiumcarboxymethyl cellulose, mixtures of microcrystalline cellulose and guargum, medium viscosity hydroxyethyl cellulose, agar, sodium alginate,mixtures of sodium alginate and calcium alginate, gellan gum,carrageenan gum grade iota, kappa or lambda, and medium viscosityhydroxypropylmethyl cellulose.

Medium viscosity sodium carboxymethyl cellulose corresponds to grade ofsodium carboxymethyl cellulose whose viscosity, for a 2% solution inwater at 25° C., is greater than 200 mPa·s and lower than 3100 mPa·s.

Medium viscosity hydroxyethyl cellulose corresponds to a grade ofhydroxyethyl cellulose whose viscosity, for a 2% solution in water at25° C., is greater than 250 mPa·s and lower than 6500 mPa·s. Mediumviscosity hydroxypropylmethyl cellulose corresponds to a grade ofhydroxypropylmethyl cellulose whose viscosity, for a 2% solution inwater at 20° C., is greater than 80 mPa·s. and lower than 3800 mPa·s.

Preferred suspending or viscosifying agents are xanthan gum, especiallyXantural 75™ from Kelco, hydroxyethylcellulose, especially Natrosol250M™ from Ashland, Kappa carrageenan gum, especially Gelcarin PH812™from FMC Biopolymer, and lambda carrageenan gum, especially ViscarinPH209™ from FMC Biopolymer.

In a preferred embodiment, the modified release formulation ofgamma-hydroxybutyrate comprises from 1 to 15% of viscosifying orsuspending agents, preferably from 2 to 10%, more preferably from 2 to5%, and most preferably from 2 to 3% of the formulation.

In a preferred embodiment, the modified release formulation ofgamma-hydroxybutyrate is in the form of a powder that is intended to bedispersed in water prior to administration and further comprises from 1to 15% of a suspending or viscosifying agent selected from a mixture ofxanthan gum, carrageenan gum and hydroxyethylcellulose or xanthan gumand carrageenan gum.

In a preferred embodiment, the modified release formulation ofgamma-hydroxybutyrate is in the form of a powder that is intended to bedispersed in water prior to administration and further comprises: from1.2 to 15% of an acidifying agent selected from malic acid and tartaricacid; and from 1 to 15% of a suspending or viscosifying agent selectedfrom a mixture of xanthan gum, carrageenan gum and hydroxyethylcelluloseor xanthan gum and carrageenan gum.

In a most preferred embodiment, the modified release formulation ofgamma-hydroxybutyrate comprises about 1% of lambda carrageenan gum orViscarin PH209™, about 1% of medium viscosity grade of hydroxyethylcellulose or Natrosol 250M™, and about 0.7% of xanthan gum or Xantural75™. For a 4.5 g dose unit, these percentages will typically equate toabout 50 mg xanthan gum (Xantural 75™), about 75 mg carrageenan gum(Viscarin PH209™) and about 75 mg hydroxyethylcellulose (Natrasol250M™).

Alternative packages of viscosifying or suspending agents, for a 4.5 gdose, include about 50 mg xanthan gum (Xantural 75™) and about 100 mgcarrageenan gum (Gelcarin PH812™), or about 50 mg xanthan gum (Xantural75™), about 75 mg hydroxyethylcellulose (Natrasol 2 50M™), and about 75mg carrageenan gum (Viscarin PH109™).

In a preferred embodiment, the modified release formulation ofgamma-hydroxybutyrate further comprises a lubricant or a glidant,besides the immediate release and modified release particles ofgamma-hydroxybutyrate. Preferred lubricants and glidants are chosen fromthe group consisting of salts of stearic acid, in particular magnesiumstearate, calcium stearate or zinc stearate, esters of stearic acid, inparticular glyceryl monostearate or glyceryl palmitostearate, stearicacid, glycerol behenate, sodium stearyl fumarate, talc, and colloidalsilicon dioxide.

The preferred lubricant or glidant is magnesium stearate.

The lubricant or glidant may be used in the particulate formulation inan amount of from 0.1 to 5%. The preferred amount is about 0.5%.

Most preferably, the modified release formulation ofgamma-hydroxybutyrate comprises about 0.5% of magnesium stearate.

A preferred modified release formulation of gamma-hydroxybutyratefurther comprises an acidifying agent. The acidifying agent helps toensure that the release profile of the formulation in 0.1N HCl willremain substantially unchanged for at least 15 minutes after mixing,which is approximately the maximum length of time a patient mightrequire before consuming the dose after mixing the formulation with tapwater.

In one particular sub-embodiment the formulation is a powder, andfurther comprising an acidifying agent and a suspending or viscosifyingagent, preferably in the weight percentages recited herein.

The preferred acidifying agents are chosen from the group consisting ofmalic acid, citric acid, tartaric acid, adipic acid, boric acid, maleicacid, phosphoric acid, ascorbic acid, oleic acid, capric acid, caprylicacid, and benzoic acid. In a preferred embodiment, the acidifying agentis present in the formulation from 1.2 to 15%, preferably from 1.2 to10%, preferably from 1.2 to 5%. Preferred acidifying agents are tartaricacid and malic acid, with malic acid being most preferred.

When tartaric acid is employed, it is preferably employed in an amountof from 1 to 10%, from 2.5 to 7.5%, or about 5%. In a most preferredembodiment, the amount of malic acid in the modified release formulationof gamma-hydroxybutyrate is from 1.2 to 15%, preferably from 1.2 to 10%,preferably from 1.2 to 5%, and most preferably 1.6% or 3.2%.

In a most preferred embodiment, the amount of malic acid in the modifiedrelease formulation of gamma hydroxybutyrate is about 1.6%.

The modified release formulation of gamma-hydroxybutyrate preferablyincludes an immediate release portion and a modified release portion ofgamma-hydroxybutyrate, and in a particularly preferred embodiment, theformulation is a particulate formulation that includes a plurality ofimmediate release gamma-hydroxybutyrate particles and a plurality ofmodified release gamma-hydroxybutyrate particles. The molar ratio ofgamma-hydroxybutyrate in the immediate release and modified releaseportions preferably ranges from 0.11:1 to 1.86:1, from 0.17:1 to 1.5:1,from 0.25:1 to 1.22:1, from 0.33:1 to 1.22:1, from 0.42:1 to 1.22:1,from 0.53:1 to 1.22:1, from 0.66:1 to 1.22:1, from 0.66:1 to 1.5:1, from0.8:1 to 1.22:1, and preferably is about 1:1. The molar percentage ofgamma-hydroxybutyrate in the immediate release portion relative to thetotal of gamma-hydroxybutyrate in the formulation preferably ranges from10% to 65%, from 15 to 60%, from 20 to 55%, from 25 to 55%, from 30 to55%, from 35 to 55%, from 40 to 55%, from 40 to 60%, or from 45 to 55%,preferably from 40% to 60%. In a preferred embodiment, the molarpercentage of the gamma-hydroxybutyrate in the immediate release portionrelative to the total of gamma-hydroxybutyrate in the formulation isabout 50%. The molar percentage of gamma-hydroxybutyrate in the modifiedrelease portion relative to the total of gamma-hydroxybutyrate in theformulation preferably ranges from 90% to 35%, from 85 to 40%, from 80to 45%, from 75 to 45%, from 70 to 45%, from 65 to 45%, from 60 to 45%,from 60 to 40%, or from 55 to 45%, preferably from 60% to 40%. In apreferred embodiment, the molar ratio of the gamma-hydroxybutyrate inthe modified release portion relative to the total ofgamma-hydroxybutyrate in the formulation is about 50%. The weightpercentage of the IR microparticles relative to the total weight of IRmicroparticles and MR microparticles, preferably ranges from 7.2% to58.2%, from 11.0% to 52.9%, from 14.9% to 47.8%, from 18.9% to 47.8%,from 23.1% to 47.8%, from 27.4% to 47.8%, from 31.8% to 47.8%, from31.8% to 52.9%, or from 36.4% to 47.8%. In other embodiments, the weightpercentage of the IR microparticles relative to the total weight of IRmicroparticles and MR microparticles preferably ranges from 5.9% to63.2%, from 9.1% to 58.1%, from 12.4% to 53.1%, from 19.9% to 53.1%,from 19.6% to 53.1%, from 23.4% to 53.1%, from 27.4% to 53.1% from 27.4%to 58.1%, preferably from 31.7% to 53.1%.

In a preferred embodiment, the finished formulation comprises 50% of itssodium oxybate content in immediate-release particles consisting of80.75% w/w of sodium oxybate, 4.25% w/w of Povidone K30 and 15% ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to 450 microns and 50% of its sodium oxybate content inmodified release particles consisting of 10.5% w/w of microcrystallinecellulose spheres with a volume mean diameter of about 95 microns toabout 450 microns, layered with 56.5% w/w of sodium oxybate mixed with3% w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 18% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 4% of methacrylic acid copolymer type C (Eudragit™ L100-55or equivalent) and 8% of methacrylic acid copolymer type B (Eudragit™S100 or equivalent).

In a preferred embodiment, the finished formulation comprises 50% of itssodium oxybate content in immediate-release particles consisting of80.75% w/w of sodium oxybate, 4.25% w/w of Povidone K30 and 15% ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to 170 microns and 50% of its sodium oxybate content inmodified release particles consisting of 10.5% w/w of microcrystallinecellulose spheres with a volume mean diameter of about 95 microns toabout 170 microns, layered with 56.5% w/w of sodium oxybate mixed with3% w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 18% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 4% of methacrylic acid copolymer type C (Eudragit™ L100-55or equivalent) and 8% of methacrylic acid copolymer type B (Eudragit™S100 or equivalent).

In a preferred embodiment, the finished formulation comprises 50% of itssodium oxybate content in immediate-release particles consisting of80.75% w/w of sodium oxybate, 4.25% w/w of Povidone K30 and 15% ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 450 microns and 50% of its sodium oxybate content inmodified release particles consisting of 11.3% w/w of microcrystallinecellulose spheres with a volume mean diameter of about 95 microns toabout 450 microns, layered with 60.5% w/w of sodium oxybate mixed with3.2% w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 15% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 0.75% of methacrylic acid copolymer type C (Eudragit™L100-55 or equivalent) and 9.25% of methacrylic acid copolymer type B(Eudragit™ S100 or equivalent).

In a preferred embodiment, the finished formulation comprises 50% of itssodium oxybate content in immediate-release particles consisting of80.75% w/w of sodium oxybate, 4.25% w/w of Povidone™ K30 and 15% ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 170 microns and 50% of its sodium oxybate content inmodified release particles consisting of 11.3% w/w of microcrystallinecellulose spheres with a volume mean diameter of about 95 microns toabout 170 microns, layered with 60.5% w/w of sodium oxybate mixed with3.2% w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 15% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 0.75% of methacrylic acid copolymer type C (Eudragit™L100-55 or equivalent) and 9.25% of methacrylic acid copolymer type B(Eudragit™ S 100 or equivalent).

In a preferred embodiment, the finished formulation comprises 50% of itsgamma-hydroxybutyrate content in immediate-release particles consistingof 80.75% w/w of potassium salt of gamma-hydroxybutyric acid, 4.25% w/wof Povidone K30 and 15% of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 450 microns and 50% ofits gamma-hydroxybutyrate content in modified release particlesconsisting of 10.5% w/w of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 450 microns, layeredwith 56.5% w/w of sodium oxybate mixed with 3% w/w of Povidone™ K30 andfinally coated with a coating composition consisting of 18% w/w ofhydrogenated vegetable oil (Lubritab™ or equivalent), 4% of methacrylicacid copolymer type C (Eudragit™ L100-55 or equivalent) and 8% ofmethacrylic acid copolymer type B (Eudragit™ S100 or equivalent).

In a preferred embodiment, the finished formulation comprises 50% of itsgamma-hydroxybutyrate content in immediate-release particles consistingof 80.75% w/w of potassium salt of gamma-hydroxybutyric acid, 4.25% w/wof Povidone K30 and 15% of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 170 microns and 50% ofits gamma-hydroxybutyrate content in modified release particlesconsisting of 10.5% w/w of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 170 microns, layeredwith 56.5% w/w of sodium oxybate mixed with 3% w/w of Povidone™ K30 andfinally coated with a coating composition consisting of 18% w/w ofhydrogenated vegetable oil (Lubritab™ or equivalent), 4% of methacrylicacid copolymer type C (Eudragit™ L100-55 or equivalent) and 8% ofmethacrylic acid copolymer type B (Eudragit™ S100 or equivalent).

In a preferred embodiment, the finished formulation comprises 16.7% ofits gamma-hydroxybutyrate content in immediate-release particlesconsisting of 80.75% w/w of potassium salt of gamma-hydroxybutyric acid,4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose sphereswith a volume mean diameter of about 95 microns to about 450 microns,16.7% of its gamma-hydroxybutyrate content in immediate-releaseparticles consisting of 80.75% w/w of magnesium salt ofgamma-hydroxybutyric acid, 4.25% w/w of Povidone K30 and 15% ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 450 microns, 16.7% of its gamma-hydroxybutyratecontent in immediate-release particles consisting of 80.75% w/w ofcalcium salt of gamma-hydroxybutyric acid, 4.25% w/w of Povidone K30 and15% of microcrystalline cellulose spheres with a volume mean diameter ofabout 95 microns to about 450 microns and 50% of itsgamma-hydroxybutyrate content in modified release particles consistingof 10.5% w/w of microcrystalline cellulose spheres with a volume meandiameter of about 95 microns to about 450 microns, layered with 56.5%w/w of sodium oxybate mixed with 3% w/w of Povidone™ K30 and finallycoated with a coating composition consisting of 18% w/w of hydrogenatedvegetable oil (Lubritab™ or equivalent), 4% of methacrylic acidcopolymer type C (Eudragit™ L100-55 or equivalent) and 8% of methacrylicacid copolymer type B (Eudragit™ S100 or equivalent).

In a preferred embodiment, the finished formulation comprises 16.7% ofits gamma-hydroxybutyrate content in immediate-release particlesconsisting of 80.75% w/w of potassium salt of gamma-hydroxybutyric acid,4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose sphereswith a volume mean diameter of about 95 microns to about 170 microns,16.7% of its gamma-hydroxybutyrate content in immediate-releaseparticles consisting of 80.75% w/w of magnesium salt ofgamma-hydroxybutyric acid, 4.25% w/w of Povidone K30 and 15% ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 170 microns, 16.7% of its gamma-hydroxybutyratecontent in immediate-release particles consisting of 80.75% w/w ofcalcium salt of gamma-hydroxybutyric acid, 4.25% w/w of Povidone K30 and15% of microcrystalline cellulose spheres with a volume mean diameter ofabout 95 microns to about 170 microns and 50% of itsgamma-hydroxybutyrate content in modified release particles consistingof 10.5% w/w of microcrystalline cellulose spheres with a volume meandiameter of about 95 microns to about 170 microns, layered with 56.5%w/w of sodium oxybate mixed with 3% w/w of Povidone™ K30 and finallycoated with a coating composition consisting of 18% w/w of hydrogenatedvegetable oil (Lubritab™ or equivalent), 4% of methacrylic acidcopolymer type C (Eudragit™ L100-55 or equivalent) and 8% of methacrylicacid copolymer type B (Eudragit™ S100 or equivalent).

In a preferred embodiment, the finished formulation comprises 50% of itsgamma-hydroxybutyrate content in immediate-release particles consistingof 80.75% w/w of potassium salt of gamma-hydroxybutyric acid, 4.25% w/wof Povidone K30 and 15% of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 450 microns and 50% ofits gamma-hydroxybutyrate content in modified release particlesconsisting of 10.5% w/w of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 450 microns, layeredwith 56.5% w/w of calcium salt of gamma-hydroxybutyric acid mixed with3% w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 18% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 4% of methacrylic acid copolymer type C (Eudragit™ L100-55or equivalent) and 8% of methacrylic acid copolymer type B (Eudragit™S100 or equivalent).

In a preferred embodiment, the finished formulation comprises 50% of itsgamma-hydroxybutyrate content in immediate-release particles consistingof 80.75% w/w of potassium salt of gamma-hydroxybutyric acid, 4.25% w/wof Povidone K30 and 15% of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 170 microns and 50% ofits gamma-hydroxybutyrate content in modified release particlesconsisting of 10.5% w/w of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 170 microns, layeredwith 56.5% w/w of calcium salt of gamma-hydroxybutyric acid mixed with3% w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 18% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 4% of methacrylic acid copolymer type C (Eudragit™ L100-55or equivalent) and 8% of methacrylic acid copolymer type B (Eudragit™S100 or equivalent).

Other Characteristics of Immediate Release Portion

The immediate release portion of the formulation may take any formcapable of achieving an immediate release of the gamma-hydroxybutyratewhen ingested. For example, when the formulation is a particulateformulation, the formulation may include unmodified “raw”gamma-hydroxybutyrate, rapidly dissolving gamma-hydroxybutyrategranules, particles or microparticles comprised of a core covered by agamma-hydroxybutyrate loaded layer containing a binder such as povidone.

The IR granules or particles of gamma-hydroxybutyrate may be made usingany manufacturing process suitable to produce the required particles,including:

-   -   agglomeration of the gamma-hydroxybutyrate sprayed preferably in        the molten state, such as the Glatt ProCell™ technique,    -   extrusion and spheronization of the gamma-hydroxybutyrate,        optionally with one or more physiologically acceptable        excipients,    -   wet granulation of the gamma-hydroxybutyrate, optionally with        one or more physiologically acceptable excipients,    -   compacting of the gamma-hydroxybutyrate, optionally with one or        more physiologically acceptable excipients,    -   granulation and spheronization of the gamma-hydroxybutyrate,        optionally with one or more physiologically acceptable        excipients, the spheronization being carried out for example in        a fluidized bed apparatus equipped with a rotor, in particular        using the Glatt CPS™ technique,    -   spraying of the gamma-hydroxybutyrate, optionally with one or        more physiologically acceptable excipients, for example in a        fluidized bed type apparatus equipped with zig-zag filter, in        particular using the Glatt MicroPx™ technique, or    -   spraying, for example in a fluidized bed apparatus optionally        equipped with a partition tube or Wurster tube, the        gamma-hydroxybutyrate, optionally with one or more        physiologically acceptable excipients, in dispersion or in        solution in an aqueous or organic solvent on a core.

Preferably, the immediate release portion of the formulation is in theform of microparticles comprising the immediate releasegamma-hydroxybutyrate and optional pharmaceutically acceptableexcipients. In a preferred embodiment, the immediate releasemicroparticles of gamma-hydroxybutyrate have a volume mean diameterD(4,3) of from 10 to 1000 microns, preferably from 95 to 600 microns,more preferably from 150 to 400 microns. Most preferably their volumemean diameter is about 270 microns.

The preferred immediate release particles of gamma-hydroxybutyrate ofthe present invention comprises a core and a layer deposited on the corethat contains the gamma-hydroxybutyrate. The core may be any particlechosen from the group consisting of:

-   -   crystals or spheres of lactose, sucrose (such as Compressuc™ PS        from Tereos), microcrystalline cellulose (such as Avicel™ from        FMC Biopolymer, Cellet™ from Pharmatrans or Celphere™ from Asahi        Kasei), sodium chloride, calcium carbonate (such as Omyapure™ 35        from Omya), sodium hydrogen carbonate, dicalcium phosphate (such        as Dicafos™ AC 92-12 from Budenheim) or tricalcium phosphate        (such as Tricafos™ SC93-15 from Budenheim);    -   composite spheres or granules, for example sugar spheres        comprising sucrose and starch (such as Suglets™ from NP Pharm),        spheres of calcium carbonate and starch (such as Destab™ 90 S        Ultra 250 from Particle Dynamics) or spheres of calcium        carbonate and maltodextrin (such as Hubercal™ CCG4100 from        Huber).

The core may also comprise other particles of pharmaceuticallyacceptable excipients such as particles of hydroxypropyl cellulose (suchas Klucel™ from Aqualon Hercules), guar gum particles (such as Grinsted™Guar from Danisco), xanthan particles (such as Xantural™ 180 from CPKelco).

According to a particular embodiment of the invention, the cores aresugar spheres or microcrystalline cellulose spheres, such as Cellets™90, Cellets™ 100 or Cellets™ 127 marketed by Pharmatrans, or alsoCelphere™ CP 203, Celphere™ CP305, Celphere™ SCP 100. Preferably thecore is a microcrystalline cellulose sphere. Most preferably the core isa Cellets™ 127 from Pharmatrans.

The core preferably has a mean volume diameter of about 95 to about 450microns, preferably about 95 to about 170 microns, most preferably about140 microns.

The layer deposited onto the core comprises the immediate releasegamma-hydroxybutyrate. Preferably the layer also comprises a binder,which may be chosen from the group consisting of:

-   -   low molecular weight hydroxypropyl cellulose (such as Klucel™ EF        from Aqualon-Hercules), low molecular weight hydroxypropyl        methylcellulose (or hypromellose) (such as Methocel™ E3 or E5        from Dow), or low molecular weight methylcellulose (such as        Methocel™ A15 from Dow);    -   low molecular weight polyvinyl pyrrolidone (or povidone) (such        as Plasdone™ K29/32 from ISP or Kollidon™ 30 from BASF), vinyl        pyrrolidone and vinyl acetate copolymer (or copovidone) (such as        Plasdone™: S630 from ISP or Kollidon™ VA 64 from BASF);    -   dextrose, pregelatinized starch, maltodextrin; and mixtures        thereof.

Low molecular weight hydroxypropyl cellulose corresponds to grades ofhydroxypropyl cellulose having a molecular weight of less than 800,000g/mol, preferably less than or equal to 400,000 g/mol, and in particularless than or equal to 100,000 g/mol. Low molecular weight hydroxypropylmethylcellulose (or hypromellose) corresponds to grades of hydroxypropylmethylcellulose the solution viscosity of which, for a 2% solution inwater and at 20° C., is less than or equal to 1,000 mPa·s, preferablyless than or equal to 100 mPa·s and in particular less than or equal to15 mPa·s. Low molecular weight polyvinyl pyrrolidone (or povidone)corresponds to grades of polyvinyl pyrrolidone having a molecular weightof less than or equal to 1,000,000 g/mol, preferably less than or equalto 800,000 g/mol, and in particular less than or equal to 100,000 g/mol.

Preferably, the binding agent is chosen from low molecular weightpolyvinylpyrrolidone or povidone (for example, Plasdone™ K29/32 fromISP), low molecular weight hydroxypropyl cellulose (for example, Klucel™EF from Aqualon-Hercules), low molecular weight hydroxypropylmethylcellulose or hypromellose (for example, Methocel™ E3 or E5 fromDow) and mixtures thereof.

The preferred binder is povidone K30 or K29/32, especially Plasdone™K29/32 from ISP. The binder may be present in an amount of 0 to 80%, 0to 70%, 0 to 60%, 0 to 50%, 0 to 40%, 0 to 30%, 0 to 25%, 0 to 20%, 0 to15%, 0 to 10%, or from 1 to 9%, most preferably 5% of binder based onthe total weight of the immediate release coating.

The preferred amount of binder is 5% of binder over the total mass ofgamma-hydroxybutyrate and binder.

The layer deposited on the core may represent at least 10% by weight,and even greater than 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75,80, 85 or 90% by weight of the total weight of the immediate releaseparticle of gamma-hydroxybutyrate. Most preferably, the layer depositedon the core represents about 85% of the weight of the immediate releaseparticle of gamma-hydroxybutyrate.

According to a preferred embodiment, the immediate-release particlescomprise 80.75% w/w of gamma-hydroxybutyrate, 4.25% w/w of Povidone K30and 15% of microcrystalline cellulose spheres.

According to a preferred embodiment, the immediate-release particlescomprise 80.75% w/w of gamma-hydroxybutyrate, 4.25% w/w of Povidone K30and 15% of microcrystalline cellulose spheres with a volume meandiameter of about 95 microns to about 450 microns.

According to a preferred embodiment, the immediate-release particlescomprise 80.75% w/w of gamma-hydroxybutyrate, 4.25% w/w of Povidone K30and 15% of microcrystalline cellulose spheres with a volume meandiameter of about 95 microns to about 170 microns.

According to a preferred embodiment, the immediate-release particlescomprise 80.75% w/w of sodium oxybate, 4.25% w/w of Povidone K30 and 15%of microcrystalline cellulose spheres.

According to another preferred embodiment, the immediate-releaseparticles comprise 80.75% w/w of potassium salt of gamma-hydroxybutyricacid, 4.25% w/w of Povidone K30 and 15% of microcrystalline cellulosespheres.

According to another preferred embodiment, the immediate-releaseparticles comprise 80.75% w/w of calcium salt of gamma-hydroxybutyricacid, 4.25% w/w of Povidone K30 and 15% of microcrystalline cellulosespheres.

According to another preferred embodiment, the immediate-releaseparticles comprise 80.75% w/w of magnesium salt of gamma-hydroxybutyricacid, 4.25% w/w of Povidone K30 and 15% of microcrystalline cellulosespheres.

According to another embodiment, the immediate-release particles aremanufactured by dissolving the gamma-hydroxybutyrate and the PovidoneK30 in a mixture of water/ethanol 40/60 w/w and spraying the resultingsolution onto the surface of the microcrystalline cellulose spheres.

Other Characteristics of Modified Release Portion

The modified release portion may be any formulation that provides thedesired in vitro dissolution profile of gamma-hydroxybutyrate. Themodified release portion is preferably comprised of modified releaseparticles, obtained by coating immediate release particles ofgamma-hydroxybutyrate with a coating (or coating film) that inhibits theimmediate release of the gamma-hydroxybutyrate. In one sub-embodimentthe modified release portion comprises particles comprising: (a) aninert core; (b) a coating; and (c) a layer comprising the gammahydroxybutyrate interposed between the core and the coating.

In a preferred embodiment, the modified release portion comprises atime-dependent release mechanism and a pH-dependent release mechanism.

In a preferred embodiment, the coating film comprises at least onepolymer carrying free carboxylic groups, and at least one hydrophobiccompound preferably characterized by a melting point equal or greaterthan 40° C.

The polymer carrying free carboxylic groups is preferably selected from:(meth)acrylic acid/alkyl (meth)acrylate copolymers or methacrylic acidand methylmethacrylate copolymers or methacrylic acid and ethyl acrylatecopolymers or methacrylic acid copolymers type A, B or C, cellulosederivatives carrying free carboxylic groups, preferably celluloseacetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, carboxymethylethyl cellulose, cellulose acetatetrimellitate, hydroxypropyl methyl cellulose acetate succinate,polyvinyl acetate phthalate, zein, shellac, alginate and mixturesthereof.

In a preferred embodiment, the methacrylic acid copolymers are chosenfrom the group consisting of poly (methacrylic acid, methylmethacrylate) 1:1 or Eudragit™ L100 or equivalent, poly (methacrylicacid, ethyl acrylate) 1:1 or Eudragit™ L00-55 or equivalent and poly(methacrylic acid, methyl methacrylate) 1:2 or Eudragit™ 100 orequivalent.

In another sub-embodiment the coating comprises a polymer carrying freecarboxylic groups wherein the free carboxylic groups are substantiallyionized at pH 7.5.

The hydrophobic compound with a melting point equal or greater than 40°C. may be selected from the group consisting of hydrogenated vegetableoils, vegetable waxes, wax yellow, wax white, wax microcrystalline,lanolin, anhydrous milk fat, hard fat suppository base, lauroyl macrogolglycerides, polyglyceryl diisostearate, diesters or triesters ofglycerol with a fatty acid, and mixtures thereof.

Even more preferably, the hydrophobic compound with a melting pointequal or greater than 40° C. is chosen from the group of followingproducts: hydrogenated cottonseed oil, hydrogenated soybean oil,hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil,candellila wax, tristearin, tripalmitin, trimyristin, yellow wax, hardfat or fat that is useful as suppository bases, anhydrous dairy fats,lanolin, glyceryl palmitostearate, glyceryl stearate, lauryl macrogolglycerides, polyglyceryl diisostearate, diethylene glycol monostearate,ethylene glycol monostearate, omega 3 fatty acids, and mixtures thereof.A particularly preferred subgroup of products comprises hydrogenatedcottonseed oil, hydrogenated soybean oil, hydrogenated palm oil,glyceryl behenate, hydrogenated castor oil, candelilla wax, tristearin,tripalmitin, trimyristin, beeswax, hydrogenated poly-1 decene, carnaubawax, and mixtures thereof.

In practice, and without this being limiting, it is preferable thehydrophobic compound with a melting point equal or greater than 40° C.to be chosen from the group of products sold under the followingtrademarks: Dynasan™, Cutina™, Hydrobase™, Dub™ Castorwax™, Croduret™,Compritol™, Sterotex™, Lubritab™, Apifil™, Akofine™ Softisan™,Hydrocote™, Livopol™, Super Hartolan™, MGLA™, Corona™, Protalan™Akosoft™, Akosol™, Cremao™, Massupol™, Novata™, Suppocire™, Wecobee™Witepsol™, Lanolin™, Incromega™, Estaram™, Suppoweiss™, Gelucire™,Precirol™ Emulcire™, Plurol diisostéarique™, Geleol™, Hydrine™,Monthyle™, Kahlwax™ and mixtures thereof; and, preferably, from thegroup of products sold under the following trademarks: Dynasan™ P60,Dynasan™114, Dynasan™116, Dynasan™118, Cutina™ HR, Hydrobase™ 66-68,Dub™ HPH, Compritol™ 888, Sterotex™ NF, Sterotex™ K, Lubritab™, andmixtures thereof.

A particularly suitable coating is composed of a mixture of hydrogenatedvegetable oil and a methacrylic acid copolymer. The exact structure andamount of each component, and the amount of coating applied to theparticle, controls the release rate and release triggers. Eudragit®methacrylic acid copolymers, namely the methacrylic acid-methylmethacrylate copolymers and the methacrylic acid-ethyl acrylatecopolymers, have a pH-dependent solubility: typically, the pH triggeringthe release of the active ingredient from the microparticles is set bythe choice and mixture of appropriate Eudragit® polymers. In the case ofgamma hydroxybutyrate modified release microparticles, the theoreticalpH triggering the release is preferably from 5.5 to 6.97 or 6.9, morepreferably 6.5 up to 6.9. By “pH trigger” is meant the minimum pH abovewhich dissolution of the polymer occurs.

In a particular embodiment, the coating comprises a hydrophobic compoundwith a melting point equal or greater than 40° C. and a polymer carryingfree carboxylic groups are present in a weight ratio from 0.4 or 0.5 to4, preferably from 0.6 or 0.67 to 2.5, most preferably from 0.6 or 0.67to 2.33; most preferably about 1.5.

A particularly suitable coating is composed of a mixture of hydrogenatedvegetable oil and a methacrylic acid copolymer with a theoretical pHtriggering the release from 6.5 up to 6.97 in a weight ratio from 0.4 or0.5 to 4, preferably from 0.6 or 0.67 to 2.5, most preferably from 0.6or 0.67 to 2.33; most preferably of about 1.5.

The modified release particles of gamma-hydroxybutyrate preferably havea volume mean diameter of from 100 to 1200 microns, from 100 to 500microns, from 200 to 800 microns, and preferably of about 320 microns.

The coating may preferably represent 10 to 50%, 15 to 45%, 20 to 40%, or25 to 35% by weight of the total weight of the coated modified releaseparticles. Preferably, the coating represents 25-30% by weight of thetotal weight of the modified release particles of gamma-hydroxybutyrate.

In a preferred embodiment, the coating layer of the modified releaseparticles of gamma-hydroxybutyrate is obtained by spraying, inparticular in a fluidized bed apparatus, a solution, suspension ordispersion comprising the coating composition as defined previously ontothe immediate release particles of gamma-hydroxybutyrate, in particularthe immediate release particles of gamma-hydroxybutyrate as previouslydescribed. Preferably, the coating is formed by spraying in a fluidizedbed equipped with a Wurster or partition tube and according to an upwardspray orientation or bottom spray a solution of the coating excipientsin hot isopropyl alcohol.

According to a preferred embodiment, the modified release particles ofgamma-hydroxybutyrate consist of 10.5% w/w of microcrystalline cellulosespheres with a volume mean diameter of about 95 microns to about 450microns, layered with 56.5% w/w of gamma-hydroxybutyrate mixed with 3%w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 18% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 4% of methacrylic acid copolymer type C (Eudragit™ L100-55or equivalent) and 8% of methacrylic acid copolymer type B (Eudragit™S100 or equivalent), all percentages expressed based on the total weightof the final modified release particles of gamma-hydroxybutyrate.

According to a preferred embodiment, the modified release particles ofgamma-hydroxybutyrate consist of 10.5% w/w of microcrystalline cellulosespheres with a volume mean diameter of about 95 microns to about 170microns, layered with 56.5% w/w of gamma-hydroxybutyrate mixed with 3%w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 18% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 4% of methacrylic acid copolymer type C (Eudragit™ L100-55or equivalent) and 8% of methacrylic acid copolymer type B (Eudragit™S100 or equivalent), all percentages expressed based on the total weightof the final modified release particles of gamma-hydroxybutyrate.

According to a preferred embodiment, the modified release particles ofgamma-hydroxybutyrate consist of 10.5% w/w of microcrystalline cellulosespheres with a volume mean diameter of about 95 microns to about 450microns, layered with 56.5% w/w of sodium oxybate mixed with 3% w/w ofPovidone™ K30 and finally coated with a coating composition consistingof 18% w/w of hydrogenated vegetable oil (Lubritab™ or equivalent), 4%of methacrylic acid copolymer type C (Eudragit™ L100-55 or equivalent)and 8% of methacrylic acid copolymer type B (Eudragit™ S100 orequivalent), all percentages expressed based on the total weight of thefinal modified release particles of sodium oxybate.

According to a preferred embodiment, the modified release particles ofgamma-hydroxybutyrate consist of 10.5% w/w of microcrystalline cellulosespheres with a volume mean diameter of about 95 microns to about 170microns, layered with 56.5% w/w of sodium oxybate mixed with 3% w/w ofPovidone™ K30 and finally coated with a coating composition consistingof 18% w/w of hydrogenated vegetable oil (Lubritab™ or equivalent), 4%of methacrylic acid copolymer type C (Eudragit™ L100-55 or equivalent)and 8% of methacrylic acid copolymer type B (Eudragit™ S100 orequivalent), all percentages expressed based on the total weight of thefinal modified release particles of sodium oxybate.

According to another preferred embodiment, the modified releaseparticles of gamma-hydroxybutyrate consist of 11.3% w/w ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 450 microns, layered with 60.5% w/w ofgamma-hydroxybutyrate mixed with 3.2% w/w of Povidone™ K30 and finallycoated with a coating composition consisting of 15% w/w of hydrogenatedvegetable oil (Lubritab™ or equivalent), 0.75% of methacrylic acidcopolymer type C (Eudragit™ L100-55 or equivalent) and 9.25% ofmethacrylic acid copolymer type B (Eudragit™ S100 or equivalent).

According to another preferred embodiment, the modified releaseparticles of gamma-hydroxybutyrate consist of 11.3% w/w ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 170 microns, layered with 60.5% w/w ofgamma-hydroxybutyrate mixed with 3.2% w/w of Povidone™ K30 and finallycoated with a coating composition consisting of 15% w/w of hydrogenatedvegetable oil (Lubritab™ or equivalent), 0.75% of methacrylic acidcopolymer type C (Eudragit™ L100-55 or equivalent) and 9.25% ofmethacrylic acid copolymer type B (Eudragit™ S100 or equivalent).

According to another preferred embodiment, the modified releaseparticles of gamma-hydroxybutyrate consist of 11.3% w/w ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 450 microns, layered with 60.5% w/w of sodiumoxybate mixed with 3.2% w/w of Povidone™ K30 and finally coated with acoating composition consisting of 15% w/w of hydrogenated vegetable oil(Lubritab™ or equivalent), 0.75% of methacrylic acid copolymer type C(Eudragit™ L100-55 or equivalent) and 9.25% of methacrylic acidcopolymer type B (Eudragit™ S100 or equivalent).

According to another preferred embodiment, the modified releaseparticles of gamma-hydroxybutyrate consist of 11.3% w/w ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 170 microns, layered with 60.5% w/w of sodiumoxybate mixed with 3.2% w/w of Povidone™ K30 and finally coated with acoating composition consisting of 15% w/w of hydrogenated vegetable oil(Lubritab™ or equivalent), 0.75% of methacrylic acid copolymer type C(Eudragit™ L100-55 or equivalent) and 9.25% of methacrylic acidcopolymer type B (Eudragit™ S100 or equivalent).

Packaging

The modified release formulation of gamma-hydroxybutyrate is preferablysupplied in dose packets, sachets, or stick-packs comprising aparticulate formulation. The particulate formulation may be a powder fororal suspension. The sachets or dose packets are preferably available inseveral different doses, comprising gamma-hydroxybutyrate in amountsequivalents to 0.5 g, 1.0 g, 1.5 g, 3.0 g, 4.5 g, 6.0 g, 7.5 g, 9.0 g,10.5 g and/or 12 g of sodium oxybate. In an embodiment, each nightlydose packet contains a composition comprising a blend ofimmediate-release and controlled-release granules providing doses of 4.5g, 6 g, 7.5 g, or 9 g of gamma-hydroxybutyrate. The composition mayfurther include microcrystalline cellulose spheres, povidone K30,hydrogenated vegetable oil, methacrylic acid copolymer, malic acid,xanthan gum, hydroxyethyl cellulose, carrageenan, and/or magnesiumstearate. Depending on the dose required, one or more of these packetsmay be opened, and its contents mixed with tap water to provide thenightly dose of gamma-hydroxybutyrate. Dose packets may contain a singledose of the composition provided in 4.5 g, 6 g, 7.5 g, and 9 g doses. Insome embodiments, the dose packet may be mixed with about 1%4 cup water,⅓ cup water, 1%2 cup water, 50 mL water, or 25 mL water. In at least oneexample, the dose packet is mixed with ⅓ cup water (about 80 mL) to forman oral suspension for administration to the patient. In at least oneadditional example, the dose packet is mixed with about 50 mL in amixing cup to form an oral suspension for administration to the patient.The mixing cup may be additionally filled with about 25 mL afteradministration of the oral suspension to suspend any remainingcomposition in the mixing cup to form a second oral suspension foradministration to the patient. In other examples, only one suspensionmay be needed to administer the full dosage to the patient. Suspensionsmay be consumed within 30 minutes.

In some embodiments, nightly dose packets 104 containing the compositionmay be provided to a patient in a nightly dose packet storage system100. The nightly dose packet storage system 100 may include into a30-day supply carton 102 (e.g. FIGS. 91-97 ) or a 7-day supply carton103 (e.g. FIG. 129 ), between 7 and 30 nightly dose packets 104 (e.g.FIGS. 119-125 ), between one and four nightly dose packet containers 110(e.g. FIGS. 112-118 ), a mixing cup 108 (e.g. FIGS. 105-111 ), and amixing cup receptacle (e.g. FIG. 98-104 or 130 ).

FIGS. 119-125 show example nightly dose packets 104. The nightly dosepackets 104 may be child resistant. The nightly dose packet may includea cut or tear line 105 near the upper portion of the nightly dose packet104. There may be an indicator (e.g. scissors) near the cut line 105 tomark the cut line 105. In some examples, the nightly dose packet 104 mayalso be operable to be folded longitudinally, perpendicular to the cutline 105, to allow the patient to tear the dose packet without the needfor scissors. In this example, the nightly dose packet 104 may includeone or more perforations 106 or a portion of weaker material to assistthe tearing of the dose packet when folded longitudinally. For example,as seen in FIGS. 119-125 , the nightly dose packet 104 may include agray box to indicate where the perforations 106 are located. A ceramiccylinder may be used to create the perforations that can be torn byhand. Each nightly dose packet may include an expiration date.

As seen in FIGS. 91-132 , the sachets or nightly dose packets 104 may bepackaged with a mixing cup 108 (e.g. mixing aid or dosing cup) formixing the composition in the sachet or dose packet 104 with water tofor a suspension. The dose packets 104 may be first assembled into aonce-nightly dose packet container 110 (e.g. FIGS. 112-118 ), and thenone or more once-nightly dose packet containers 110 may then beassembled into a larger 30-day supply carton 102 (e.g. FIGS. 91-97 ) ora 7-day supply carton 103 (e.g. FIG. 129 ). The nightly dose packetcontainer 110 may be operable to hold up to 7 once-nightly dose packets104. The nightly dose packet container 110 may include a notch 116 toaid in removing the nightly dose packets 104 from the container 110. Thenightly dose packet container 110 may be removable from the largersupply carton 102, 103 for the patient's convenience (e.g. moving,traveling, or putting by the patient's bedside) and to allow the patientto track usage (e.g. one container per week). Being able to track usagemay be particularly important for patients with memory issues.

In some embodiments, the 30-day or 7-day supply carton include a notchon the top lid/flap to aid in opening the carton. The 30-day or 7-daysupply carton 102, 103 may further include an expiration date thatmatches the expiration date on the dose packets within. In someexamples, the 30-day or 7-day supply carton 102, 103 may include atamper-evident seal. The 30-day or 7-day supply carton 102, 103 mayinclude a tray 112 operable to rest on the top of the nightly dosepacket containers 110, the mixing cup receptacle 109, and/or the mixingcup 108. In some embodiments, the tray 112 may be formed by one of fourflaps for closing the 30-day or 7-day supply carton 102, 103. In atleast one example, the front facing flap of the carton 102, 103 includesa crease to fold the flap inward to form the tray 112 inset from the topof the carton. In some examples, the crease may be about ¾ in from theedge of the carton opening. The tray 112 may be operable to rest on thetop of one or more dose packet containers 110, mixing cup receptacle109, and/or mixing cup 108. The tray 112 may be operable to holdinstructions for use for the formulation or any other relevant material.In some embodiments, the front facing flap may further include a cutoutportion between the crease and the edge of the carton opening. Thecutout may align with the notch on the top lid/flap when all flaps arefolded to close the carton to aid in opening the carton via the notch.

In some embodiments, the mixing cup 108 (e.g. FIGS. 105-111 ) may beassembled into a mixing cup receptacle 109 (e.g. FIGS. 98-104 ), whichmay then be assembled into the larger 30-day or 7-day supply cartons102, 103 (e.g. FIGS. 126-132 ). The mixing cup receptacle 109 mayinclude a cup retaining portion 111 operable for holding the mixing cup108. The mixing cup receptacle 109 may further include a packet portion113 for holding up to two once-nightly dose packets (e.g. FIGS. 126-128) or only hold the mixing cup (e.g. FIGS. 130-132 ). In some examples,the cup retaining portion 111 may include a platform to elevate themixing cup within the mixing cup receptacle 109. The platform may beformed from a back wall of the mixing cup receptacle 109 such that theback wall is folded in to the cup retaining portion 111.

In some embodiments, the mixing cup 108 may have a child-resistant cap.In other embodiments, the mixing cup 108 may have a quarter turn lid. Invarious embodiments, the mixing cup 108 may be pre-marked with filllines for the water, such that the patient does not have to measure theamount of water to mix with the dose packet. For example, the mixing cup108 may include a first fill line 114 for measuring a first portion ofwater to mix and suspend the composition in a nightly dose packet 104.The mixing cup 108 may further include at least one additional markingfor measuring additional water for suspending any remnant compositionremaining in the pre-marked mixing cup after administration of thesuspension to the patient. The patient may further administer thesuspension of the additional water with the remnant composition toensure that the patient receives the full dosage of the composition. Forexample, the mixing cup 108 may include a second fill line 115 formeasuring a second portion of water to mix any remnant composition inthe mixing cup 108. In some examples, the first fill line 114 mayindicate about 50 mL and the second fill line 115 may indicate about 25mL. In other examples, the first line 114 may mark about ⅓ cup. Asillustrated in FIGS. 105-109 , the first fill line 114 may be an “A”fill line and the second fill line 115 may be a “B” fill line. In someexamples, the “A” and “B” fill lines may be on two sides of the mixingcup.

In some embodiments, the mixing cup 108 include a resin and a polymeradditive to prevent cracking when dropped while also having a clarity tosee liquids (e.g. water) in the mixing cup at the fill lines. Forexample, the mixing cup may be made of polypropylene and a propyleneelastomer additive. In some examples, the propylene elastomer additivemay be composed of isotactic propylene repeat units with random ethylenedistribution (e.g. Vistamaxx™ Performance Polymer). The mixing cup mayinclude up to 30% of the polymer additive. In some examples, the mixingcup may be resistant to cracking when dropped from about 18 inches toabout 6 feet.

In some embodiments, the inner wall of the mixing cup may be rounded atthe point where the inner wall meets the bottom of the mixing cup.Stated another way, the intersection of the wall and the bottom of themixing cup may not be a 90 degree angle. Having a rounded or non-90degree intersection may limit adhesion of the composition to the cup.For example, less residual of the composition may be left in the cupafter administering the first suspension (i.e. the composition in thedaily dosage packet mixed with water to the first fill line) as comparedto a cup with a 90 degree angle between the wall and bottom of themixing cup. Therefore, there may be less composition remaining in thecup to mix with water filled to the second fill line.

FIGS. 133A-133D are example instructions for use of the composition in anightly dosing packet and suspension in water using the mixing cup. Asshown in FIG. 133C, a method of preparing the formulation may include,but is not limited to, opening the mixing cup by twisting the cap to theleft (counter-clockwise) to remove it, filling the mixing cup with waterup to fill line A (top line) and setting the mixing cup down on a flatsurface, opening 1 once-nightly dose packet by folding the once-nightlydose packet in half at the gray tear mark located on the back of thenightly dose packet and tearing the once-nightly dose packet open orusing scissors to cut open the nightly dose packet along the cuttingline, located on the back of the nightly dose packet, pouring the entirecontents from the once-nightly dose packet into the water filled mixingcup making sure that there is no powder left in the once-nightly dosepacket, closing the mixing cup by twisting the cap to the right(clockwise) until firmly closed, mixing the water and powder solution byshaking the closed mixing cup well for at least 60 seconds, and/ormaking sure the solution is mixed thoroughly, where the mixed solutionmay appear slightly milky with some lumps. As shown in FIG. 133D, amethod of taking the formulation in solution form may include, but isnot limited to, opening the mixing cup by twisting the cap to the left(counter-clockwise) and removing it, drinking the mixed solution within30 minutes of mixing, making sure to drink all of the mixed solution inthe mixing cup, immediately refilling the mixing cup with water up tofill line B (lower line) to mix any composition left in the mixing cup,closing the mixing cup by twisting the cap to the right (clockwise)until firmly closed, shaking the mixing cup well for 10 seconds, openingthe mixing cup by twisting the cap to the left (counter-clockwise) andremoving it, drinking the mixed solution immediately after mixing,making sure to drink all of the mixed solution in the mixing cup, and/orleaving the empty mixing cup at the patient's bedside and going tosleep. The patient may avoid getting out of bed after taking the dose.

Methods of Treatment

The invention further provides a method of treating a disorder treatablewith a pharmaceutically acceptable salt of gamma-hydroxybutyrate in ahuman subject in need thereof comprising orally administering a singlenighttime daily dose to said human amounts of gamma-hydroxybutyrateequivalent to from 3.0 to 12.0 g of gamma-hydroxybutyrate or a saltthereof in the formulation of the present invention. In someembodiments, the gamma-hydroxybutyrate salt may be a calcium salt, asodium salt, a potassium salt, and/or a magnesium salt ofgamma-hydroxybutyric acid. The invention further provides methods oftreating narcolepsy, types 1 and/or 2, by orally administering atbedtime a therapeutically effective amount of a gamma-hydroxybutyrateformulation characterized by the novel gamma-hydroxybutyratepharmacokinetics or dissolution properties of the present invention. Theformulation is suitable to be administered once daily. In some examples,the formulation is suitable to be administered once nightly. Themodified release formulation of the present invention is effective totreat narcolepsy Type 1 or Type 2, wherein said treatment of narcolepsyis defined as reducing excessive daytime sleepiness or reducing thefrequency of cataplectic attacks. The therapeutically effective amountpreferably comprises equivalents from 3.0 to 12.0 g ofgamma-hydroxybutyrate, more preferably from 4.5 to 9.0 g ofgamma-hydroxybutyrate, and most preferably 4.5, 6.0, 7.5 or 9.0 g ofgamma-hydroxybutyrate. The dosage of gamma-hydroxybutyrate may beup-titrated to a suitable effective dosage for the patient. In someembodiments, the dosage of the composition initially administered may be4.5 g gamma-hydroxybutyrate. The dosage may then be increased by about1.5 g per night at weekly intervals to an effective dosage range of 6 gto 9 g per night. The dosage may be up-titrated at a rate appropriatefor the patient. Once the desired effective dosage is reached, thedosage may remain stable.

The effectiveness of the once daily treatment may be measured by one orany combination of the following criteria:

-   -   Fewer adverse reactions/effects as compared to a patient        administered twice-nightly sodium oxybate    -   No adverse reactions/effects    -   Less or no obtundation as compared to the twice-nightly sodium        oxybate treatment    -   Less of no clinically significant respiratory depression as        compared to the twice-nightly sodium oxybate treatment    -   No profound CNS depression or severe difficulty breathing    -   No clinically significant worsening of respiratory function as        measured by apnea/hyponea index and pulse oximetry    -   Increase the mean sleep latency, preferably as determined on the        Maintenance of Wakefulness Test (MWT)    -   Statistically significant improvement on the MWT at dosages of 6        g, 7.5 g, and 9 g as compared to placebo    -   Latency to sleep onset of about 5 minutes or more than placebo    -   Improve the Clinical Global Impression (CGI) rating of        sleepiness    -   Statistically significant improvement on CGI at dosages of 6 g,        7.5 g, and 9 g as compared to placebo    -   5 times or more likely to respond as much or very much improved        on CGI-Improvement as compared to placebo    -   Decrease the number of cataplexy attacks (NCA) preferably        determined from the cataplexy frequency item in the Sleep and        Symptoms Daily Diary    -   Statistically significant improvement in mean weekly cataplexy        attacks at dosages of 6 g, 7.5 g, and 9 g as compared to placebo    -   4 or fewer mean cataplexy attacks per week as compared to        placebo    -   Decrease the disturbed nocturnal sleep (DNS), the disturbed        nocturnal events or the adverse respiratory events preferably as        determined by polysomnographic (PSG) measures of sleep        fragmentation    -   Decrease the excessive daytime sleepiness (EDS) preferably as        measured by patient report via the Epworth Sleepiness Scale        (ESS)    -   Decrease the daytime sleepiness as measured by the Maintenance        of Wakefulness Test based on EEG measures of wakefulness    -   Decrease PSG transitions from N/2 to N/3 and REM sleep to wake        and N1 sleep (as determined by C Iber, S Ancoli-Israel, A        Chesson, SF Quan. The AASM Manual for the Scoring of Sleep and        Associated Events. Westchester, IL: American Academy of Sleep        Medicine; 2007).    -   Decrease the number of arousals or wakenings, preferably        obtained from a PSG as defined by the American Academy of Sleep        Medicine    -   Improve the sleep quality, preferably obtained from one or more        of (i) the Sleep and Symptom Daily Diary, (ii) Visual Analog        Scale (VAS) for sleep quality and sleep diary, and (iii) VAS for        the refreshing nature of sleep    -   Decrease the Hypnagogic Hallucinations (HH) or sleep paralysis        (SP) symptoms in NT1 narcolepsy patients, preferably as measured        by the Sleep and Symptom Daily Diary    -   Contraindication for patients with hepatic impairment

Obtundation may refer to a dulled or reduced level of alertness orconsciousness, such that a patient that is obtunded may have a moredepressed level of consciousness and may not be fully aroused. In someexamples, obtundation may be measured based on a level of consciousnessusing scales such as but not limited to the Grady Coma Scale or theGlasgow Coma Scale. Respiratory depression may refer to slow orineffective breathing. Central nervous system (CNS) depression may referto a decreased breathing rate, decreased heart rate, and/or loss ofconsciousness. In various embodiments, “clinically significant” may meanhaving an effect on the patient's daily life. In various embodiments,“statistically significant” may refer to p<0.05.

The Maintenance of Wakefulness Test measures a patient's ability toremain awake during soporific circumstances through a daytimepolysomnographic procedure. In some examples, the MWT may be quantifiedby latency to sleep onset measured in minutes. CGI may refer to anassessment of a clinician's view of the patient's global functioningprior to and after initiating a medication. CGI-Improvement may be usedto compare the patient's clinical condition to the one week prior toinitiating the medication using a 7-point scale (e.g. 1=very muchimproved; 2=much improved; 3=minimally improved; 4=no change frombaseline; 5=minimally worse; 6=much worse; 7=very much worse).

In various embodiments, the method of treating cataplexy or excessivedaytime sleepiness (EDS) in a patient with narcolepsy includes orallyadministering a dosage of a composition comprising sodium oxybate onceper night. In some embodiments, the patient is an adult. A peak plasmaconcentration (C_(max)) following administration of one dose of thecomposition may be lower than a twice-nightly sodium oxybate treatment.For example, the C_(max) following administration of one 6 g dose may beabout 65.8 mcg/mL. There may be a steady decrease in concentrationfollowing a time to peak plasma concentration (T_(max)) approximatelytwo hours after dosing. For example, the T_(max) may be about 1.51hours.

In some embodiments, the composition may be provided in a pre-measureddosage packet for administration. In an embodiment, the composition maybe provided as a powder for oral suspension. The powder composition mayinclude immediate-release and controlled-release granules of sodiumoxybate. In some examples, the composition may further includemicrocrystalline cellulose spheres, povidone K30, hydrogenated vegetableoil, methacrylic acid copolymer, malic acid, xanthan gum, hydroxyethylcellulose, carrageenan, and/or magnesium stearate. In variousembodiments, the method may include providing the powder composition ina nightly dose packet of 4.5 g, 6 g, 7.5 g, or 9 g sodium oxybate. Themethod may further include preparing the dosage of the composition bysuspending the composition from the dose packet in water. For example,the dose packet may be suspended in approximately ⅓ cup water(approximately 80 mL) or about 50 mL. In some embodiments, the patientmay be provided with a pre-marked mixing cup for measuring the water andmixing the dose packet and water. In additional embodiments, thepre-marked mixing cup may further include at least one additionalmarking for measuring additional water for suspending any remnantcomposition remaining in the pre-marked mixing cup after administrationof the suspension of the dose packet in the water. The patient mayfurther administer the additional water with the remnant composition toensure that the patient receives the full dosage of the composition.

In various embodiments, the dosage is administered without regard formeals. For example, the composition may be administered immediatelyafter eating, up to 2 hours after eating a meal, or more than 2 hoursafter eating a meal. The meal may be an evening meal. In at least oneembodiment, the composition is prepared and administered prior tobedtime. The patient may be in bed prior to orally administering thedosage and may lie down immediately after dosing as the composition maycause the patient to fall asleep abruptly without first feeling drowsy.Patients may fall asleep within 5 minutes of taking the composition,within 15 minutes of taking the composition, within 30 minutes of takingthe composition, within 1 hour of taking the composition, within 1.5hours of taking the composition, or within 2 hours of taking thecomposition. The time it takes any individual patient to fall asleep mayvary from night to night. Patients may remain in bed following ingestionof the composition.

In some embodiments, the composition may be co-administered with asingle dose of divalproex sodium ER. In some examples, the dose ofdivalproex sodium ER may be about 1250 mg.

In a preferred embodiment, the treatment of the present invention issuperior, as measured by any one or combination of the foregoingcriteria, to an equal dose administered twice nightly of an immediaterelease liquid solution of sodium oxybate, with the second doseadministered 4 hours after the first dose. The invention furtherprovides a method of treatment of narcolepsy Type 1 or Type 2 wherein,compared to a dosing regimen consisting of administering half the doseat t₀ and another half of the dose at t_(4h) of an immediate releaseliquid solution of sodium oxybate, a single bedtime daily doseadministration of a therapeutically effective amount of the formulationof the invention has been shown to produce less confusion, lessdepressive syndrome, less incontinence, less nausea or lesssleepwalking.

Dose-Proportionality

In one additional embodiment, the present invention provides acomposition comprising an oral suspension for the treatment ofnarcolepsy or excessive daytime sleepiness, the suspension comprising ablend of granules for oral suspension in water, the granules comprisinggamma-hydroxybutyrate, wherein the oral suspension is administered onlyonce nightly and is effective to induce sleep in a human subject in needthereof for at least six hours, and wherein the composition provides aC_(max) which increases approximately 2-fold, and more than doseproportionally for AUC increasing 2.3-fold, as a total daily dose isdoubled from 4.5 g to 9 g. In some examples, the oral suspension iseffective to induce sleep in a human subject in need thereof for atleast six hours, at least seven hours, or at least eight hours. Thegranules comprising gamma-hydroxybutyrate may include any formulation ofgamma-hydroxybutyrate described herein.

In some aspects, the composition may include an amount ofgamma-hydroxybutyrate that provides the same amount ofgamma-hydroxybutyrate as 3.7 g, 5.0 g, 6.2 g, or 7.4 g of sodiumoxybate.

In some aspects, the composition further includes about 80 mL of water.The water temperature may be 50° C. or less. The composition may beconsumed within 30 minutes of mixing with water.

In some aspects, the granules may include carrageenan, hydrogenatedvegetable oil, hydroxyethyl cellulose, magnesium stearate, malic acid,methacrylic acid copolymer, microcrystalline cellulose, povidone,xanthan gum, and combinations thereof.

In some additional aspects, the granules for oral suspension in watermay be packaged in a once-nightly dose packet. The composition may beprovided in single dose packets that include 3.0 g, 4.5 g, 6 g, 7.5 g,or 9 g of gamma-hydroxybutyrate. The single dose packets may be providedas a total of 7 or 30 single dose packets per package.

In still further aspects, the composition may be provided with aprepackaged mixing cup.

The composition may be suspended in about one-third of a cup of waterprior to administration. The composition may be taken at least 2 hoursafter eating.

In one additional embodiment, the present invention provides acomposition of gamma-hydroxybutyrate comprising immediate release andmodified release portions, wherein the immediate release portioncomprises particles comprising one or more salts ofgamma-hydroxybutyrate and the modified release portion comprisesparticles comprising one or more salts of gamma-hydroxybutyrate, whereinthe particles of the modified release portion are coated with a coatingcomprising:

-   -   a. a polymer carrying free carboxylic groups, and    -   b. a hydrophobic compound having a melting point equal or        greater than 40° C.,    -   c. wherein the composition is suitable for administration only        once nightly,    -   d. wherein the composition induces sleep for at least 6        consecutive hours, and    -   e. provides a C_(max) which increases approximately 2-fold, and        more than dose proportionally for AUC increasing 2.3-fold, as a        total daily dose is doubled from 4.5 g to 9 g.

In some aspects, the amount of gamma-hydroxybutyrate in the immediaterelease portion may be equal to the amount of gamma-hydroxybutyrate inthe modified release portion. In other aspects, the ratio ofgamma-hydroxybutyrate in the immediate release portion and the modifiedrelease portion may be from 10/90 to 65/35. In some exemplaryembodiments, the ratio of gamma-hydroxybutyrate in the immediate releaseportion and the modified release portion is from 40/60 to 60/40. Thecomposition may include an amount of gamma-hydroxybutyrate that providesthe same amount of gamma-hydroxybutyrate as 3.7 g, 5.0 g, 6.2 g, or 7.4g of sodium oxybate.

The polymer carrying free carboxylic acid groups may have a pH triggerfrom 5.5 to 6.97. The free carboxylic acid groups may be ionized at pH7.5.

The granules may further include hydroxyethyl cellulose, malic acid,methacrylic acid copolymer, microcrystalline cellulose, and povidone.

The granules may further include carrageenan, hydrogenated vegetableoil, hydroxyethyl cellulose, malic acid, methacrylic acid copolymer,microcrystalline cellulose, povidone, and xanthan gum.

In some aspects, the composition may be in an amount effective to treatnarcolepsy Type 1 or Type 2, wherein said treatment of narcolepsyincludes reducing excessive daytime sleepiness, reducing the frequencyof cataplectic attacks, or a combination thereof.

In some aspects, the composition may be in an amount effective to inducesleep for at least eight hours.

In some aspects, the particles comprising the gamma-hydroxybutyrate inthe immediate release portion and the modified release portion have amean diameter from 10 to 1000 microns, and the particles ofgamma-hydroxybutyrate in the modified release portion have a meandiameter from 100 to 1200 microns. In some examples, the particlescomprising gamma-hydroxybutyrate in the immediate release portion have amean diameter from 150 to 400 microns, and the particles ofgamma-hydroxybutyrate in the modified release portion have a meandiameter from 200 to 800 microns.

The granules for oral suspension in water may be packaged in aonce-nightly dose packet. The composition may be provided in single dosepackets comprising 3.0 g, 4.5 g, 6 g, 7.5 g, or 9 g ofgamma-hydroxybutyrate. The single dose packets may be provided as atotal of 7 or 30 single dose packets.

In some additional aspects, the composition may have preferred qualitiesas compared to a twice-nightly sodium oxybate composition. Thecomposition may have a lower risk of causing a confusional state in apatient as compared to a twice-nightly sodium oxybate composition. Thecomposition may have a 50% lower risk of causing a confusional state ina patient as compared to a twice-nightly sodium oxybate composition.

Idiopathic Hypersomnia and Excessive Daytime Sleepiness Symptoms

In one additional embodiment, the present invention provides a method oftreating narcolepsy, cataplexy, or excessive daytime sleepiness in asubject comprising administering to the subject a once-nightly dose ofgamma-hydroxybutyrate, wherein 2% or fewer subjects administered theonce-nightly dose of gamma-hydroxybutyrate experience a confusionalstate. For example, 2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%,1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, or 0%of subjects administered the once-nightly dose of gamma-hydroxybutyratemay experience a confusional state. The once-nightly dosage ofgamma-hydroxybutyrate may be any formulation of gamma-hydroxybutyratedescribed herein.

In some aspects, the subject may have a reduction in symptoms related tonarcolepsy, cataplexy, or excessive daytime sleepiness. For example, thesubject may have a decreased risk of falls or headaches. The subject mayhave a decreased risk of car and work accidents. The subject may have adecreased risk of work-related errors or lack of energy. The subject mayhave a decreased risk of irritability or mood problems. The subject mayhave a decreased risk of gastrointestinal, cardiovascular, or metabolicdisorders. The subject may have a decreased risk of drug or alcoholabuse. The subject may have a decreased risk of one or more of the sleepdeprivation side effects selected form the group consisting of lack ofalertness, irritation, memory lapses, lack of focus, difficultyretaining new concepts, difficulty making decisions, slower reactiontimes, and combinations thereof. The subject may have a decreased riskof developing diabetes, obesity, and heart disease associated withlong-term sleep deprivation.

In another embodiment, the present invention provides a method oftreating narcolepsy, cataplexy, or excessive daytime sleepiness in asubject comprising administering to the subject a once-nightly dose ofgamma-hydroxybutyrate, wherein 3% or fewer subjects administered theonce-nightly dose of gamma-hydroxybutyrate experience sleepwalking. Forexample, 3%, 2.99%, 2.88%, 2.7%, 2.6%, 2.50%, 2.4%, 2.30%, 2.2%, 2.10%,2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%,0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, or 0% of subjectsadministered the once-nightly dose of gamma-hydroxybutyrate mayexperience sleepwalking. The once-nightly dosage ofgamma-hydroxybutyrate may be any formulation of gamma-hydroxybutyratedescribed herein.

In some aspects, the sleepwalking may be a parasomnia that occurs duringnon-REM sleep.

Maintenance of Wakefulness Test

In one additional embodiment, the invention provides a method oftreating narcolepsy, cataplexy, or excessive daytime sleepiness in ahuman patient in need thereof, the method comprising orallyadministering to the patient a once-nightly dosage ofgamma-hydroxybutyrate, wherein the patient has statistically significantimprovement on the Maintenance of Wakefulness Test (MWT) at dosages of4.5 g, 6 g, 7.5 g, and 9 g as compared to placebo. The once-nightlydosage of gamma-hydroxybutyrate may be any formulation ofgamma-hydroxybutyrate described herein. The MWT may measure latency tosleep onset in minutes averaged over five sessions at 2-hour intervalsfollowing nocturnal polysomnography.

In some aspects, the patient may have a latency to sleep onset about 5minutes or more than placebo. The sleep latency may be determined as thenumber of minutes a patient remains awake during the MWT.

In some additional aspects, the patient may have a reduction in weeklycataplexy attacks. The patient may have an average total reduction inweekly cataplexy attacks from about 4.00 to about 7.00 as compared toplacebo. For example, the patient may have an average total reduction inweekly cataplexy attacks from about 4.00, 4.10, 4.20, 4.30, 4.40, 4.50,4.60, 4.70, 4.80, 4.90, 5.00, 5.10, 5.20, 5.30, 5.40, 5.50, 5.60, 5.70,5.80, 5.90, 6.00, 6.10, 6.20, 6.30, 6.40, 6.50, 6.60, 6.70, 6.80, 6.90,or about 7.00. In an exemplary embodiment, the patient has an averagetotal reduction in weekly cataplexy attacks from 4.83 to 6.65 ascompared to placebo.

In further aspects, the patient may have an average improvement from4.00 minutes to 7.00 minutes in the change form baseline in the MWT ascompared to placebo. For example, the patient may have an averageimprovement of about 4.00, 4.10, 4.20, 4.30, 4.40, 4.50, 4.60, 4.70,4.80, 4.90, 5.00, 5.10, 5.20, 5.30, 5.40, 5.50, 5.60, 5.70, 5.80, 5.90,6.00, 6.10, 6.20, 6.30, 6.40, 6.50, 6.60, 6.70, 6.80, 6.90, or about7.00 minutes from baseline in the MWT as compared to placebo. In anexemplary embodiment, the patient has an average improvement from 4.98minutes to 6.21 minutes in the change from baseline in MWT as comparedto placebo.

In still further aspects, the patient may be on concomitant stimulantuse. The stimulants used may include slriamfetol, pitolisant,methylphenidate, modafinil, dextroamphetamine, amphetamine, armodafinil,lisdexamfetamine, and other CNS stimulants known in the art andcombinations thereof.

In addition to the results obtained from the MWT, the patient may alsohave a change of being much improved or very much improved in a ClinicalGlobal Impression-Improvement (CGI-I) score. In an exemplary embodiment,the patient has a 42.1 to 77.0% chance of being much improved or verymuch improved in a CGI-I score.

In another embodiment, the invention provides a method of treatingnarcolepsy, cataplexy, or excessive daytime sleepiness in a humanpatient in need thereof, the method comprising orally administering tothe patient a once-nightly dosage of gamma-hydroxybutyrate, wherein theoral administration of the once-nightly dosage induces the patient tofall asleep within 5 minutes of administration. The once-nightly dosageof gamma-hydroxybutyrate may be any formulation of gamma-hydroxybutyratedescribed herein.

In another embodiment, the invention provides a method of treatingnarcolepsy, cataplexy, or excessive daytime sleepiness in a humanpatient in need thereof, the method comprising orally administering tothe patient a once-nightly dosage of gamma-hydroxybutyrate, wherein theoral administration of the once-nightly dosage induces the patient tofall asleep within 15 minutes of administration. The once-nightly dosageof gamma-hydroxybutyrate may be any formulation of gamma-hydroxybutyratedescribed herein.

ADDITIONAL EMBODIMENTS

In one additional embodiment, the invention provides a modified releaseformulation of gamma-hydroxybutyrate, preferably comprising immediaterelease and modified release portions, wherein the formulation releases(a) at least 80% of its gamma-hydroxybutyrate at 1 hour when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.05Mmonobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C.and a paddle speed of 75 rpm, and (b) from 10% to 65%, of itsgamma-hydroxybutyrate at one hour and three hours when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm.

In a second additional embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, comprising immediaterelease and modified release portions, wherein (a) the formulationreleases at least 80% of its gamma-hydroxybutyrate at 1 hour when testedin a dissolution apparatus 2 according to USP 38 <711> in 900 mL of0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm, (b) the formulation releases from10% to 65% of its gamma-hydroxybutyrate at one hour and three hours whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speedof 75 rpm, and (c) the modified release portion releases greater than80% of its gamma-hydroxybutyrate at 3 hours in a dissolution teststarted in 750 mL of 0.1N hydrochloric acid for 2 hours then switched to950 mL 0.05M monobasic potassium phosphate buffer adjusted to pH 6.8 ata temperature of 37° C. and a paddle speed of 75 rpm.

In a third additional embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, comprising immediaterelease and modified release portions, wherein (a) the formulationreleases at least 80% of its gamma-hydroxybutyrate at 1 hour when testedin a dissolution apparatus 2 according to USP 38 <711> in 900 mL of0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm, (b) the formulation releases 10% to65%, of its gamma-hydroxybutyrate at one hour and at three hours whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speedof75 rpm, (c) the formulation releases greater than 60% of itsgamma-hydroxybutyrate at 10 hours when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm, and (d) the modifiedrelease portion releases greater than 80% of its gamma-hydroxybutyrateat 3 hours in a dissolution test started in 750 mL of 0.1N hydrochloricacid for 2 hours then switched to 950 mL 0.05M monobasic potassiumphosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm.

In a fourth additional embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, preferably comprisingimmediate release and modified release portions, wherein the formulationreleases (a) at least 80% of its gamma-hydroxybutyrate at 3 hours whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm, and (b) from 40% to 65%, of itsgamma-hydroxybutyrate at one hour and three hours when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm.

In a fifth additional embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, comprising immediaterelease and modified release portions, wherein (a) the formulationreleases at least 80% of its gamma-hydroxybutyrate at 3 hour 3 whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm, (b) the formulation releases from40% to 65% of its gamma-hydroxybutyrate at one hour and three hours whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speedof 75 rpm, and (c) the modified release portion releases greater than80% of its gamma-hydroxybutyrate at 3 hours in a dissolution teststarted in 750 mL of 0.1N hydrochloric acid for 2 hours then switched to950 mL 0.05M monobasic potassium phosphate buffer adjusted to pH 6.8 ata temperature of 37° C. and a paddle speed of 75 rpm.

In a sixth additional embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, comprising immediaterelease and modified release portions, wherein (a) the formulationreleases at least 80% of its gamma-hydroxybutyrate at 3 hours whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm, (b) the formulation releases 40% to65%, of its gamma-hydroxybutyrate at one hour and at three hours whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speedof75 rpm, (c) the formulation releases greater than 60% of itsgamma-hydroxybutyrate at 10 hours when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm, and (d) the modifiedrelease portion releases greater than 80% of its gamma-hydroxybutyrateat 3 hours in a dissolution test started in 750 mL of 0.1N hydrochloricacid for 2 hours then switched to 950 mL 0.05M monobasic potassiumphosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm.

In a seventh additional embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, preferably comprisingimmediate release and modified release portions, wherein the formulationreleases (a) at least 80% of its gamma-hydroxybutyrate at 1 hour whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm, and (b) from 40% to 65%, of itsgamma-hydroxybutyrate at one hour and three hours when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm.

In an eighth additional embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, comprising immediaterelease and modified release portions, wherein (a) the formulationreleases at least 80% of its gamma-hydroxybutyrate at 1 hour when testedin a dissolution apparatus 2 according to USP 38 <711> in 900 mL of0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm, (b) the formulation releases from40% to 65% of its gamma-hydroxybutyrate at one hour and three hours whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speedof 75 rpm, and (c) the modified release portion releases greater than80% of its gamma-hydroxybutyrate at 3 hours in a dissolution teststarted in 750 mL of 0.1N hydrochloric acid for 2 hours then switched to950 mL 0.05M monobasic potassium phosphate buffer adjusted to pH 6.8 ata temperature of 37° C. and a paddle speed of 75 rpm.

In a ninth additional embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, comprising immediaterelease and modified release portions, wherein (a) the formulationreleases at least 80% of its gamma-hydroxybutyrate at 1 hour when testedin a dissolution apparatus 2 according to USP 38 <711> in 900 mL of0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm, (b) the formulation releases 40 to65%, of its gamma-hydroxybutyrate at one hour and at three hours whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speedof75 rpm, (c) the formulation releases greater than 60% of itsgamma-hydroxybutyrate at 10 hours when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm, and (d) the modifiedrelease portion releases greater than 80% of its gamma-hydroxybutyrateat 3 hours in a dissolution test started in 750 mL of 0.1N hydrochloricacid for 2 hours then switched to 950 mL 0.05M monobasic potassiumphosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm.

EXAMPLES Example 1. Formulations

Tables 1a-1d provide the qualitative and quantitative compositions ofsodium oxybate IR microparticles, MR microparticles, and mixtures of IRand MR microparticles. The physical structure of the microparticlesshowing the qualitative and quantitative composition of the IR and MRmicroparticles is depicted in FIGS. 1A and 1B, respectively.

Briefly, sodium oxybate immediate release (IR) microparticles wereprepared as follows: 1615.0 g of sodium oxybate and 85.0 g ofpolyvinylpyrrolidone (Povidone K30-Plasdone™ K29/32 from ISP) weresolubilized in 1894.3 g of absolute ethyl alcohol and 1262.9 g of water.The solution was entirely sprayed onto 300 g of microcrystallinecellulose spheres (Cellets™ 127) in a fluid bed spray coater apparatus.IR Microparticles with volume mean diameter of about 270 microns wereobtained.

Sodium oxybate modified release (MR) microparticles were prepared asfollows: 22.8 g of methacrylic acid copolymer Type C (Eudragit™L100-55), 45.8 g of methacrylic acid copolymer Type B (Eudragit™ S100),102.9 g of hydrogenated cottonseed oil (Lubritab™), were dissolved in1542.9 g of isopropanol at 78° C. The solution was sprayed entirely onto400.0 g of the sodium oxybate IR microparticles described above in afluid bed spray coater apparatus with an inlet temperature of 48° C.,spraying rate around 11 g per min and atomization pressure of 1.3 bar.MR microparticles were dried for two hours with inlet temperature set to56° C. MR microparticles with mean volume diameter of about 320 micronswere obtained.

The finished composition, which contains a 50:50 mixture of MR and TRmicroparticles calculated on their sodium oxybate content, was preparedas follows: 353.36 g of the above JR microparticles, 504.80 g of theabove MR microparticles, 14.27 g of malic acid (D/L malic acid), 6.34 gof xanthan gum (Xantural™ 75 from Kelco), 9.51 g of carrageenan gum(Viscarin™ PH209 from FMC Biopolymer), 9.51 g of hydroxyethylcellulose(Natrosol™ 250M from Ashland) and 4.51 g of magnesium stearate weremixed. Individual samples of7.1 g (corresponding to a 4.5 g dose ofsodium oxybate with half of the dose as immediate-release fraction andhalf of the dose as modified release fraction) were weighed.

TABLE 1a Composition of IR Microparticles Quantity per ComponentFunction 2.25 g dose (g) Sodium oxybate Drug substance 2.25Microcrystalline Core 0.418 cellulose spheres Povidone K30 Binder and0.118 excipient in diffusion coating Ethyl alcohol Solvent Eliminatedduring processing Purified water Solvent Eliminated during processingTotal 2.786

TABLE 1b Composition of MR Microparticles Quantity per ComponentFunction 4.5 g dose (g) IR Microparticles Core of MR 2.786microparticles Hydrogenated Coating 0.716 Vegetable Oil excipientMethacrylic acid Coating 0.159 Copolymer Type C excipient Methacrylicacid Coating 0.318 Copolymer Type B excipient Isopropyl alcohol SolventEliminated during processing Total 3.981

TABLE 1c Qualitative Finished Composition Quantity per ComponentFunction 4.5 g dose (g) MR microparticles Modified release 3.981fraction of sodium oxybate IR microparticles Immediate release 2.786fraction of sodium oxybate Malic acid Acidifying agent 0.113 Xanthan gumSuspending agent 0.050 Hydroxyethylcellulose Suspending agent 0.075Carrageenan gum Suspending agent 0.075 Magnesium stearate Lubricant0.036 Total 7.116

TABLE 1d Quantitative finished composition Quantity per ComponentFunction 4.5 g dose (g) Sodium oxybate Drug substance 4.5Microcrystalline cellulose spheres Core 0.836 Povidone K30 Binder 0.237Hydrogenated Vegetable Oil Coating excipient 0.716 Methacrylic acidCopolymer Type C Coating excipient 0.159 Methacrylic acid Copolymer TypeB Coating excipient 0.318 Malic acid Acidifying agent 0.113 Xanthan gumSuspending agent 0.050 Hydroxyethylcellulose Suspending agent 0.075Carrageenan gum Suspending agent 0.075 Magnesium stearate Lubricant0.036 Total 7.116

Example 1bis: Alternative Formulation

An alternative formulation to the formulation described in example 1 isdescribed in Example 1bis.

Sodium oxybate immediate release (TR) microparticles were prepared bycoating the TR microparticles described in example 1 with a top coatlayer. Microparticles were prepared as follows: 170.0 of hydroxypropylcellulose (Klucel™ EF Pharm from Hercules) were solubilized in 4080.0 gof acetone. The solution was entirely sprayed onto 1530.0 g of the TRmicroparticles of Example 1 in a fluid bed spray coater apparatus. TRMicroparticles with volume mean diameter of about 298 microns wereobtained (see Table 1bis-a).

Sodium oxybate modified release (MR) microparticles were prepared asdescribed in example 1 (see Table 1b).

The finished composition, which contains a 50:50 mixture of MR and TRmicroparticles based on their sodium oxybate content, was prepared asfollows: 412.22 g of the above TR microparticles, 530.00 g of the aboveMR microparticles, 29.96 g of malic acid (D malic acid), 4.96 g ofxanthan gum (Xantural™ 75 from Kelco), 4.96 g of colloidal silicondioxide (Aerosil™ 200 from Degussa) and 9.92 g of magnesium stearatewere mixed. Individual samples of 7.45 g (corresponding to a 4.5 g doseof sodium oxybate with half of the dose in an immediate-release fractionand half of the dose in a modified release fraction) were weighed (seeTable 1bis-b and 1bis-c).

TABLE 1bis-a Composition of IR Microparticles Quantity per ComponentFunction 2.25 g dose (g) Sodium oxybate Drug substance 2.25Microcrystalline cellulose Core 0.418 spheres Povidone K30 Binder and0.118 excipient in diffusion coating Hydroxypropyl cellulose Top coat0.310 Ethyl alcohol Solvent Eliminated during processing Purified waterSolvent Eliminated during processing Acetone Solvent Eliminated duringprocessing Total 3.096

TABLE 1bis-b Qualitative Finished Composition Quantity per ComponentFunction 4.5 g dose (g) MR microparticles Modified release 3.981fraction of sodium oxybate IR microparticles Immediate release 3.096fraction of sodium oxybate Malic acid Acidifying agent 0.225 Xanthan gumSuspending agent 0.037 Colloidal silicon dioxide Gliding agent 0.037Magnesium stearate Lubricant 0.075 Total 7.451

TABLE 1bis-c Quantitative finished composition Quantity per ComponentFunction 4.5 g dose (g) Sodium oxybate Drug substance 4.5Microcrystalline cellulose spheres Core 0.836 Povidone K30 Binder 0.237Hydroxypropyl cellulose Top coat 0.310 Hydrogenated Vegetable OilCoating excipient 0.716 Methacrylic acid Copolymer Type C Coatingexcipient 0.159 Methacrylic acid Copolymer Type B Coating excipient0.318 Malic acid Acidifying agent 0.225 Xanthan gum Suspending agent0.037 Colloidal silicon dioxide Gliding agent 0.037 Magnesium stearateLubricant 0.075 Total 7.451

Compared to the finished composition described in example 1, thisalternative composition has the following characteristics: same MRmicroparticles, same IR microparticles but with a top coat, increasedamount of malic acid, only one suspending agent (xanthan gum) andpresence of a glidant.

Finished compositions from Example 1 and 1bis exhibit substantially thesame in-vitro dissolution profiles (see FIGS. 7 and 8 ).

Example 2: In Vitro Release Profiles of IR, MR and Finished Compositionsof Formulations of Examples 1 and 1bis Dissolution Testing of IRMicroparticles

The dissolution profile of 2786 mg of IR microparticles of Example 1,corresponding to 2250 mg of sodium oxybate per vessel, was determined in0.1N HCl dissolution medium using a USP apparatus 2. Dissolution mediumtemperature was maintained at 37.0±0.5° C., and the rotating paddlespeed was set at 100 rpm. The release profile of the IR microparticlesis shown in FIG. 2 and Table 2a. All the sodium oxybate was released at1 hour.

TABLE 2a Percent Sodium Oxybate Released in 0.1N HCl for IRmicroparticles of sodium oxybate prepared according to Example 1 Time(min) % released 0 0 5 94 10 97 15 97 30 98 60 98Dissolution Testing of IR Microparticles from Example 1bis

The dissolution profile of 3096 mg of IR microparticles of Example 1bis,corresponding to 2250 mg of sodium oxybate per vessel, was determined in0.1N HCl dissolution medium using a USP apparatus 2. Dissolution mediumtemperature was maintained at 37.0±0.5° C., and the rotating paddlespeed was set at 100 rpm. The release profile of the IR microparticlesis shown in FIG. 2 and Table 2b. All the sodium oxybate was released at1 hour.

TABLE 2b Percent Sodium Oxybate Released in 0.1N HCl for IRmicroparticles of sodium oxybate prepared according Example 1bis Time(min) % Released 0 0 5 91 10 99 15 100 30 101 60 100Dissolution Testing of MR Microparticles from Example 1—Protocol (2 h0.1N HCl/Phosphate Buffer pH 6.8)

49.1 g of MR microparticles from Example 1 were mixed with 0.5 g ofmagnesium stearate (from Peter Graven) and 0.25 g of colloidal silicondioxide (Aerosil™ 200 from Evonik). The dissolution profile of 4040 mgof the mixture which corresponds to 2250 mg of sodium oxybate per vesselwas determined using the USP apparatus 2. Dissolution medium temperaturewas maintained at 37.0±0.5° C., and the rotating paddle speed was set at75 rpm.

After 2 hours in 750 mL of 0.1N HCl medium, 6.5 g of monobasic potassiumphosphate was added to the dissolution vessel. pH and volume were thenrespectively adjusted to 6.8 and 950 mL, as needed by the addition ofNaOH and water. The potassium phosphate concentration was equal to 0.05M in the dissolution medium after pH and volume adjustment.

The release profile of the MR microparticles is shown in FIG. 3 andTable 2c. The sodium oxybate was not released in the 0.1N HCldissolution medium during two hours. After the switch to pH 6.8dissolution medium, all the sodium oxybate was released within 30minutes.

TABLE 2c Percent Sodium Oxybate Released in two sequential dissolutionmedia (0.1 HCl for 2 hours, then phosphate buffer pH 6.8) for MRmicroparticles of sodium oxybate prepared according to Example 1 Time(h) % released 0 0 1 1 2 2 2.25 33 2.5 97 3 103 4 104 6 103

FIG. 4 overlays the dissolution profile of the MR microparticles ofExample 1 with the dissolution profile for MR microparticles reported inSupernus U.S. Pat. No. 8,193,211, FIG. 3 . It shows that the dissolutionprofiles are different and that the MR microparticles according to thepresent invention release greater than 80% of their sodium oxybate at 3hours, whereas the MR microparticles described in Supernus U.S. Pat. No.8,193,211, FIG. 3 do not and exhibit a much slower release profile.

Dissolution Testing of Finished Composition According to Example 1 inDeionized Water

The dissolution profile of the quantity equivalent to 4.5 g sodiumoxybate of the finished composition according Example 1 was determinedin 900 mL of deionized water using the USP apparatus 2. The dissolutionmedium was maintained at 37.0±0.5° C. and the rotating paddle speed wasfixed at 50 rpm. The release profile is shown in FIG. 5 and Table 2d.The IR fraction of sodium oxybate was solubilized in 15 minutes. Therelease of sodium oxybate from the modified-release fraction startedafter approximately 4 hours with 90% of the total dose released at 6hours.

TABLE 2d Percent Sodium Oxybate Released in deionized water for finishedcomposition of sodium oxybate prepared according to Example 1 Time (h) %released 0 0 0.25 53 1 52 2 54 3 55 4 58 5 69 6 92 7 96 8 97

An overlay of the release profile of the finished formulation of Example1 versus that reported in USP 2012/0076865 FIG. 2 is shown in FIG. 6 .It shows that the dissolution profiles are different. The formulationdescribed in USP 2012/0076865 FIG. 2 does not exhibit a lag phase afterthe dissolution of the immediate release part.

Release Testing of Different Batches of MR Microparticles and FinishedDosage Forms

In vitro release profiles obtained in 900 mL of 0.1N HCl dissolutionmedium for different batches of modified release (MR) microparticlesprepared according to Example 1 are described below in Table 2e. Thedissolution profile of 4040 mg of microparticles corresponding to 2250mg of sodium oxybate per vessel is determined using the USP apparatus 2.Dissolution medium temperature was maintained at 37.0 □ 0.5° C., and therotating paddle speed was set at 100 rpm.

TABLE 2e Percent Sodium Oxybate Released in 0.1N HCl Dissolution Mediumfrom different manufacturing lots of MR Particles of Example 1 Time Lot1 Lot 2 Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 0.25 2.22 0.62 0.42 0.860.56 1.03 0.69 0.26 1.0 2.59 1.14 1.23 1.48 0.96 2.15 1.43 0.97 2.003.07 1.71 2.09 1.94 1.36 3.16 2.17 1.39 3 3.55 2.31 2.75 2.29 1.76 4.082.82 1.80 4.0 4.23 3.03 3.53 2.75 2.18 4.92 3.50 2.31 6 7.99 7.68 8.695.33 3.78 7.52 5.70 8.10 8.0 37.44 33.84 33.84 26.20 17.00 21.59 21.0237.27 10 77.09 69.85 65.51 61.77 49.89 50.98 53.48 67.64 12 91.26 85.7284.25 83.55 77.65 75.68 78.00 82.66 16 96.15 90.48 95.35 97.34 96.9495.19 96.17 90.35

In vitro release profiles obtained in 0.1N HCl for three batches offinished composition comprising IR (50% w/w sodium oxybate dose) and MRmicroparticles (50% w/w sodium oxybate dose), prepared as described inExample 1, are provided in Table 2f. The sodium oxybate dose per vesselwas 4.5 g, 6 g and 7.5 g respectively and dissolution was determined in900 mL of 0.1N HCl dissolution medium using the USP apparatus 2. Thedissolution medium was maintained at 37.0±0.5° C. and the rotatingpaddle speed was fixed at 100 rpm. Single dose units were poured in acontainer containing 50 mL of tap water. After 5 minutes, the suspensionwas poured in the dissolution vessel containing 840 mL of 0.1N HCldissolution medium. 10 mL of water were used to rinse the container andwere added to the dissolution vessel.

TABLE 2f Percent Sodium Oxybate Released in 0.1N HCl Dissolution Mediumfor three batches of finished composition prepared according to Example1 Time (hour) Batch 1 Batch 2 Batch 3 0.5 50 49 50 1 50 50 50 3 50 50 506 52 52 53 8 61 64 63 12 90 93 97 16 96 94 95

FIG. 7 and Table 2 g depict dissolution profiles determined using a USPapparatus 2 in a 900 mL in 0.1N HCl dissolution medium of four finishedcompositions, two prepared according to Example 1 and two preparedaccording to Example 1bis. The dissolution medium was maintained at37.0±0.5° C. and the rotating paddle speed was fixed at 100 rpm. Itshows that the composition according to the invention releases from 10to 65% of its sodium oxybate at 1 and 3 hours and releases greater than60% at 10 hours.

TABLE 2g Percent Sodium Oxybate Released in 0.1N HCl Dissolution Mediumfor four batches of finished compositions, two prepared according toExample 1 and two prepared according to Example 1bis Time ExampleExample (hour) 1bis 1bis Example 1 Example 1 0  0  0  0  0 0.25 Nd Nd 5250 0.5 51 50 Nd Nd 1 51 50 54 51 3 51 50 54 52 6 55 52 55 53 8 72 61 6057 10 Nd Nd 73 70 12 86 90 85 83 16 88 96 96 94 20 Nd Nd 99 98 Nd: notdetermined

FIG. 8 and Table 2 h depict dissolution profiles determined using a USPapparatus 2 in a 900 mL phosphate buffer pH 6.8 dissolution medium forfour finished compositions prepared according to Example 1 or 1bis. Thedissolution medium was maintained at 37.0±0.5° C. and the rotatingpaddle speed was fixed at 100 rpm. It shows that the compositionaccording to the invention releases more than 80% of its sodium oxybateat 3 hours.

TABLE 2h Percent Sodium Oxybate Released in phosphate buffer pH 6.8Dissolution Medium for four batches of finished compositions, twoprepared according to Example 1 and two prepared according to Example1bis Example Example Time (hour) 1bis 1bis Example 1 Example 1 0  0  0 0  0 0.25 Nd Nd  75  84 0.5  99  98 Nd Nd 1 101 101 100 102 1.5 101 101106 108 2 100 100 Nd Nd 3 103 100 Nd Nd 4 103 100 Nd Nd 6 102  99 101102 8 103  99 101 105 10 103  99 101 Nd 12 101  99 101 102 16 Nd Nd 100101 20 Nd Nd  99  98 Nd: not determined

Release Testing of MR Microparticles and Finished Compositions—Effect ofPaddle Speed:

FIG. 9 and Table 2i depict dissolution profiles in 0.1N HCl of a batchof MR microparticles prepared according to Example 1. The dissolutionprofile of 4040 mg of microparticles corresponding to 2250 mg of sodiumoxybate per vessel was determined using the USP apparatus 2. Thedissolution medium temperature was maintained at 37.0±0.5° C., and therotating paddle speed was set at 75 or 100 rpm.

TABLE 2i Percent Sodium Oxybate Released in 0.1N HCl Dissolution Mediumfor MR microparticles prepared according to Example 1 Time (hour) 75 rpm100 rpm 0 0 0 0.25 1 1 1 2 1 2 2 2 3 3 2 4 3 3 6 6 5 8 28 26 10 65 62 1286 84 16 97 97

FIG. 10 and Table 2j depict dissolution profiles in 0.1N HCl of afinished composition prepared according to Example 1. The dose pervessel was 4.5 g and dissolution was determined in 900 mL of dissolutionmedium using the USP apparatus 2. The dissolution medium temperature wasmaintained at 37.0±0.5° C. and the rotating paddle speed was set at 75or 100 rpm.

Single dose units were poured in a container containing 50 mL of tapwater. After 5 minutes, the suspension was poured in the dissolutionvessel containing 840 mL of 0.1N HCl medium. 10 mL of water were used torinse the container and were added to the dissolution vessel.

TABLE 2j Percent Sodium Oxybate Released in 0.1N HCl Dissolution Mediumfor finished composition prepared according to Example 1 Time (hour) 75rpm 100 rpm 0 0 0 0.25 48 47 1 53 52 3 54 53 6 56 56 8 65 65 10 82 79 1292 89 16 97 96 20 98 98

Example 3. In Vivo Pharmacokinetic Study of Finished CompositionAccording to Example 1bis

Pharmacokinetic testing was undertaken in vivo in healthy humanvolunteers according to the principles described in FDA's March 2003Guidance for Industry on BIOAVAILABILITY AND BIOEQUIVALENCE STUDIES FORORALLY ADMINISTERED DRUG PRODUCTS—GENERAL CONSIDERATIONS. All testingwas performed in subjects two hours after eating a standardized dinner.Xyrem® doses were administered in two equipotent doses four hours apart.All other tested doses were manufactured as described in Example 1bis.The standardized dinner consisted of 25.5% fat, 19.6% protein, and 54.9%carbohydrates.

The finished composition of Example 1bis given as a 4.5 g once-nightlydose rather than a standard Xyrem® dosing twice (2×2.25 g) nightly 4hours apart, produced a dramatically different pharmacokinetic profilethan Xyrem® as shown in FIG. 11 . As summarized below (Tables 3a and3b), 4.5 g nighttime doses of finished composition of the inventionequivalent to twice-nightly doses of Xyrem® (2×2.25 g) provided somewhatless total exposure to sodium oxybate with a later median Tmax than theinitial Xyrem® dose. The relative bioavailability was about 88%.Composition according to the invention avoids the high second-dose peakconcentration of Xyrem® and therefore does not exhibit the substantialbetween-dose fluctuations in concentration, while achieving a comparablemean C8 h.

TABLE 3a Pharmacokinetic Parameters of finished composition of Example1bis vs. Xyrem ® Mean Cmax (μg/mL) Mean AUCinf Median Tmax (hour) (% CV)(h*μg/mL) (min-max) Finished composition 44.35 (38) 188.88 (44) 1.5(0.5-4) of Example 1bis 4.5 g Xyrem ® 2 × 2.25 g 1st dose: 33.41 (41)214.32 (48) 1st dose: 1.00 (0.5-2) 2nd dose: 65.91 (40) 2nd dose: 4.50(4.33-6.5)

TABLE 3b Mean plasma concentration of gamma-hydroxybutyrate(microgram/mL) versus time of finished composition of Example 1bis andXyrem ® Finished composition Finished composition Example 1bis 4.5 gExample 1bis 6.0 g Finished composition (2 h after meal) (2 h aftermeal) Example 1bis 7.5 g Xyrem ® Time pooled mean pooled mean (2 h aftermeal) (2 × 2.25 g) (hour) (N = 26) (N = 19) (N = 11) part I (N = 15) 00.00 0.00 0.00 0.00 0.5 29.31 36.44 43.19 27.44 1 34.93 49.97 63.3228.97 1.5 36.63 54.66 73.40 26.12 2 36.78 54.82 67.96 21.11 2.5 33.3553.05 66.59 NA 3 30.28 50.25 62.13 13.93 3.5 27.30 47.22 59.45 10.25 423.66 43.06 57.40 6.92 4.5 19.89 39.13 50.85 57.33 5 16.55 34.28 45.0952.27 5.5 13.62 32.11 44.94 43.55 6 12.40 25.84 42.36 35.20 6.5 11.2522.36 41.02 27.44 7 11.27 18.07 40.76 19.36 7.5 9.65 15.41 35.83 13.88 86.86 12.80 30.94 9.24 10 1.08 2.38 7.99 2.64 12 NC 0.52 1.47 NC NC: NotCalculated

The pharmacokinetic profile of a single 6 g dose of finished compositionproduced according to Example 1bis was also tested and found to have asimilar pharmacokinetic profile as the 4.5 g dose. FIG. 12 provides apharmacokinetic profile comparison of a single 4.5 g or 6 g dose offinished composition according to Example 1bis in the same 7 subjects.The pharmacokinetic profile for a 7.5 g dose of finished formulationproduced according to Example 1bis was also obtained. FIG. 13 and Table3c provide data on a single 4.5 g, 6 g and 7.5 g dose, showing effectson Tmax, Cmax, C8 h, AUC8 h and AUCinf related to dose strength. The 7.5g dose achieved a mean C8 h equal to about 31 microgram/mL whichrepresents approximately 128.5% of the C8 h obtained for Xyrem® dosed2×3.75 g which was extrapolated to be approximately 24.07 microgram/mLfrom published data. The 7.5 g dose achieved a ratio of AUC8 h to AUCinfof about 0.89, whereas the ratio was 0.83 and 0.93 for the 4.5 g and 6 gdoses respectively.

TABLE 3c Pharmacokinetic Parameters of 4.5 g, 6 g, and 7.5 g of finishedcomposition produced according to Example 1bis Finished composition MeanC_(max) Mean AUC_(inf) Mean AUC_(8h) Mean C_(8h) according to Example(μg/mL) (h*μg/mL) (h*μg/mL) Median T_(max) (μg/mL) 1bis (% CV) (% CV) (%CV) (h) (min-max) (% CV) 4.5 g 44.35 (38) 188.88 (47) 174.68 (48) 1.5(0.5-4)  6.86 (84)   6 g 65.46 (35) 307.34 (48) 290.97 (47)     3(0.5-5.5)  12.8 (82) 7.5 g 88.21 (30) 454.99 (34) 404.88 (31)   2(0.5-6) 30.94 (34)

FIG. 14 and table 3d compare the pharmacokinetic parameters AUCinf andC8 h obtained for 7.5 g of a finished composition according to Example1bis to the same parameters calculated for 2×4.5 g, i.e. 9 g total doseof Xyrem®. The data show that a 7.5 g dose of a formulation according tothe invention given once nightly exhibits a similar PK profile to 9 g ofXyrem® given in two separate equal doses.

TABLE 3d Pharmacokinetic Parameters of 7.5 g of finished compositionproduced according to Example 1bis compared to 2 × 4.5 g of Xyrem ®Ratio (%) AUC_(inf) Ratio (%) C_(8h) Mean C_(8h) Mean AUC_(inf)composition to composition to C_(8h) (μg/mL) (μg/mL*h) AUC_(inf) Xyrem ®Xyrem ® Xyrem ® 2 × 4.5 g 28.9 518 NA NA Finished composition 30.9 45588% 107% according to Example 1bis 7.5 g

Example 4. Alternative Formulation

Tables 4a-4d provide the qualitative and quantitative compositions of IRmicroparticles, MR microparticles, and mixtures of IR and MRmicroparticles. The physical structure of the microparticles showing thequalitative and quantitative composition of the IR and MR microparticlesis depicted in FIGS. 15A and 15B, respectively.

Briefly, sodium oxybate immediate release (IR) microparticle wereprepared as follows: 1615.0 g of Sodium Oxybate and 85.0 g ofpolyvinylpyrrolidone (Povidone K30-Plasdone™ K29/32 from ISP) weresolubilized in 1894.3 g of absolute ethyl alcohol and 1262.9 g of water.The solution was entirely sprayed onto 300 g of microcrystallinecellulose spheres (Cellets™ 127) in a fluid bed spray coater apparatus.IR microparticles with volume mean diameter of about 270 microns wereobtained.

Sodium oxybate modified release (MR) microparticles were prepared asfollows: 4.0 g of Methacrylic acid copolymer Type C (Eudragit™ L100-55),49.3 g of Methacrylic acid copolymer Type B (Eudragit™ S100), 80 g ofHydrogenated cottonseed oil (Lubritab™), were dissolved in 1200.0 g ofisopropanol at 78° C. The solution was sprayed entirely on 400.0 g of IRmicroparticles prepared above in a fluid bed spray coater apparatus withan inlet temperature 48° C., spraying rate around 11 g per min andatomization pressure 1.3 bar. MR microparticles were dried for two hourswith inlet temperature set to 56° C. MR microparticles with volume meandiameter of about 330 microns were obtained.

The finished composition, which contained a 50:50 mixture of MR and IRmicroparticles calculated on their sodium oxybate content, was preparedas follows: 27.86 g of IR microparticles, 37.15 g of MR microparticles,1.13 g of malic acid (D/L malic acid), 0.50 g of xanthan gum (Xantural™75 from Kelco), 0.75 g of carrageenan gum (Viscarin™ PH209 from FMCBiopolymer), 0.75 g of hydroxyethylcellulose (Natrosol™ 250M fromAshland) and 0.34 g of magnesium stearate were mixed. Individual samplesof 6.85 g (corresponding to a 4.5 g sodium oxybate dose with half of thedose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

TABLE 4a Composition of IR Microparticles Quantity per ComponentFunction 2.25 g dose (g) Sodium oxybate Drug substance 2.25 Microcrystalline cellulose Core 0.418 spheres Povidone K30 Binder andexcipient in 0.118 diffusion coating Ethyl alcohol Solvent Eliminatedduring processing Purified water Solvent Eliminated during processingTotal 2.786

TABLE 4b Composition of MR Microparticles Quantity per ComponentFunction 2.25 g dose (g) IR Microparticles Core of MR 2.786Microparticles Hydrogenated Vegetable Oil Coating excipient 0.557Methacrylic acid Copolymer Coating excipient 0.028 Type C Methacrylicacid Copolymer Coating excipient 0.344 Type B Isopropyl alcohol SolventEliminated during processing Total 3.715

TABLE 4c Qualitative Finished Composition Quantity per ComponentFunction 4.5 g dose (g) MR microparticles Modified release fraction3.715 of sodium oxybate IR microparticles Immediate release fraction2.786 of sodium oxybate Malic acid Acidifying agent 0.113 Xanthan gumSuspending agent 0.050 Hydroxyethylcellulose Suspending agent 0.075Carrageenan gum Suspending agent 0.075 Magnesium stearate Lubricant0.034 Total 6.848

TABLE 4d Quantitative finished composition Quantity per ComponentFunction 4.5 g dose (g) Sodium oxybate Drug substance 4.5  Microcrystalline cellulose Core 0.836 spheres Povidone K30 Binder 0.237Hydrogenated Vegetable Oil Coating excipient 0.557 Methacrylic acidCopolymer Coating excipient 0.028 Type C Methacrylic acid CopolymerCoating excipient 0.344 Type B Malic acid Acidifying agent 0.113 Xanthangum Suspending agent 0.050 Hydroxyethylcellulose Suspending agent 0.075Carrageenan gum Suspending agent 0.075 Magnesium stearate Lubricant0.034 Total 6.848

Example 4bis

An alternative formulation to example 4 is described in example 4bis.Sodium oxybate immediate release (IR) microparticles were prepared bycoating the IR microparticles described in example 4 with a top coatlayer. IR Microparticles were prepared as follows: 170.0 ofhydroxypropyl cellulose (Klucel™ EF Pharm from Hercules) weresolubilized in 4080.0 g of acetone. The solution was entirely sprayedonto 1530.0 g of the IR microparticles of Example 4 in a fluid bed spraycoater apparatus. IR Microparticles with volume mean diameter of about298 microns were obtained (see Table 4bis-a).

Sodium oxybate modified release (MR) microparticles were prepared asdescribed in example 4 (see Table 4b).

The finished composition, which contains a 50:50 mixture of MR and IRmicroparticles calculated based on sodium oxybate content, was preparedas follows: 424.99 g of the above IR microparticles, 509.98 g of theabove MR microparticles, 30.89 g of malic acid (D/L malic acid), 4.93 gof xanthan gum (Xantural™ 75 from Kelco), 4.93 g of colloidal silicondioxide (Aerosil™ 200 from Degussa) and 9.86 g of magnesium stearatewere mixed. Individual samples of 7.18 g (corresponding to a 4.5 g doseof sodium oxybate with half of the dose as an immediate-release fractionand half of the dose as a modified release fraction) were weighed. (seeTables 4bis-b and 4bis-c).

TABLE 4bis-a Composition of IR Microparticles Quantity per ComponentFunction 2.25 g dose (g) Sodium oxybate Drug substance 2.25 Microcrystalline cellulose Core 0.418 spheres Povidone K30 Binder andexcipient 0.118 in diffusion coating Hydroxypropyl cellulose Top coat0.310 Ethyl alcohol Solvent Eliminated during processing Purified waterSolvent Eliminated during processing Acetone Solvent Eliminated duringprocessing Total 3.096

TABLE 4bis-b Qualitative Finished Composition Quantity per ComponentFunction 4.5 g dose (g) MR microparticles Modified release fraction of3.715 sodium oxybate IR microparticles Immediate release fraction of3.096 sodium oxybate Malic acid Acidifying agent 0.225 Xanthan gumSuspending agent 0.036 Colloidal silicon dioxide Gliding agent 0.036Magnesium stearate Lubricant 0.072 Total 7.180

TABLE 4bis-c Quantitative finished composition Quantity per ComponentFunction 4.5 g dose (g) Sodium oxybate Drug substance 4.5  Microcrystalline cellulose spheres Core 0.836 Povidone K30 Binder 0.237Hydroxypropyl cellulose Top coat 0.310 Hydrogenated Vegetable OilCoating excipient 0.557 Methacrylic acid Copolymer Type C Coatingexcipient 0.028 Methacrylic acid Copolymer Type B Coating excipient0.344 Malic acid Acidifying agent 0.225 Xanthan gum Suspending agent0.036 Colloidal silicon dioxide Gliding agent 0.036 Magnesium stearateLubricant 0.072 Total 7.180

Compared to the finished composition described in example 4, thisalternative composition has the following characteristics: same MRmicroparticles, same TR microparticles but with a top coat, increasedamount of malic acid, only one suspending agent (xanthan gum) andpresence of a glidant.

Example 5 In Vitro Release Profiles of IR, MR and Finished Compositionsof Formulation of Example 4 and 4bis

Dissolution Testing of MR Microparticles from Example 4—Protocol (2 h0.1N HCl/Phosphate Buffer pH 6.8)

49.1 g of MR microparticles from Example 4 were mixed with 0.5 g ofmagnesium stearate (from Peter Greven) and 0.25 g of colloidal silicondioxide (Aerosil™ 200 from Evonik).

The dissolution profile of 3770 mg of the mixture which correspond to2250 mg of sodium oxybate per vessel was determined using the USPapparatus 2. Dissolution medium temperature was maintained at 37.0±0.5°C., and the rotating paddle speed was set at 75 rpm.

After 2 hours in 750 mL of 0.1N HCl dissolution medium, 6.5 g ofmonobasic potassium phosphate was added in the dissolution vessel. pHand volume were then respectively adjusted to 6.8 and 950 mL. Thepotassium phosphate concentration was equal to 0.05 M in the dissolutionmedium after pH and volume adjustment. The release profile is shown inFIG. 16 and Table 5a.

TABLE 5a Percent Sodium Oxybate Released in two sequential dissolutionmedia (0.1N HCl for two hours, then phosphate buffer pH 6.8) for MRmicroparticles of sodium oxybate prepared according to Example 4 %sodium Time (h) oxybate dissolved 0 0 1 1 2 2 2.25 9 2.5 40 3 89 4 102 6103

The sodium oxybate was not released in the 0.1N HCl medium during twohours. After the switch at pH 6.8, 40% of the API was released after 30minutes and 90% of API after 1 hour. FIG. 17 overlays the dissolutionprofile of the MR microparticles of Example 4 with the dissolutionprofile for MR microparticles reported in Supernus U.S. Pat. No.8,193,211, FIG. 3 . It shows that the dissolution profiles are differentand especially that the MR microparticles according to the inventionrelease greater than 80% of its sodium oxybate at 3 hours, whereas theMR microparticles described in Supernus U.S. Pat. No. 8,193,211, FIG. 3do not and exhibit a much slower releasing profile.

Dissolution Testing of Finished Composition According to Example 4 inDeionized Water:

The dissolution profile of the quantity equivalent to 4.5 g of sodiumoxybate of the finished composition of the Example 4 was determined in900 mL of deionized water using the USP apparatus 2. The dissolutionmedium was maintained at 37.0±0.5° C. and the rotating paddle speed wasset at 50 rpm. The release profile of is shown in FIG. 18 and Table 5b.

TABLE 5b Percent Sodium Oxybate Released in deionized water for finishedcomposition of sodium oxybate prepared according to Example 4 Time(hour) Example 4 0 0 0.25 52 1 55 2 53 3 54 4 52 5 54 6 60 7 78 8 90

The IR fraction of sodium oxybate was solubilized in 15 minutes. Therelease of sodium oxybate from the modified release fraction startedafter 5 hours with 90% of the total dose released at 8 hours.

An overlay of the release profile of the finished composition of theExample 4 versus that reported in USP 2012/0076865 FIG. 2 is shown inFIG. 19 . It shows that the dissolution profiles are different. Theformulation described in USP 2012/0076865 FIG. 2 does not exhibit a lagphase after the dissolution of the immediate release part.

FIG. 20 and Table 5c depict dissolution profiles determined using a USPapparatus 2 in a 900 mL in 0.1N HCl dissolution medium of three finishedcompositions prepared according to Example 4bis. The dissolution mediumwas maintained at 37.0±0.5° C. and the rotating paddle speed was fixedat 100 rpm. It shows that the composition according to the inventionreleases from 10 to 65% of its sodium oxybate at 1 and 3 hours andreleases greater than 60% at 10 hours.

TABLE 5c Percent Sodium Oxybate Released in 0.1N HCl Dissolution Mediumfor three batches of finished composition prepared according to Example4bis Time (Hour) Batch 1 Batch 2 Batch 3 0 0 0 0 0.25 50 Nd Nd 0.5 51 5049 0.75 51 Nd Nd 1 51 51 51 1.5 51 Nd Nd 2 51 Nd Nd 3 51 52 53 4 51 NdNd 6 55 57 57 8 74 70 71 10 89 Nd Nd 12 93 90 92 16 94 95 97 Nd = notdetermined

FIG. 21 and Table 5d depict dissolution profile determined using a USPapparatus 2 in a 900 mL phosphate buffer pH 6.8 dissolution medium for afinished composition prepared according to Example 4bis. The dissolutionmedium was maintained at 37.0±0.5° C. and the rotating paddle speed wasset at 100 rpm. It shows that the composition according to the inventionreleases more than 80% of its sodium oxybate at 3 hours.

TABLE 5d Percent Sodium Oxybate Released in phosphate buffer pH 6.8Dissolution Medium for finished composition prepared according toExample 4bis Time (Hour) Example 4bis 0 0 0.25 54 0.5 54 0.75 55 1.0 561.5 63 2 77 3 103 4 105 6 105 8 102 10 101 12 104 16 100

Example 6. In Vivo Pharmacokinetic Study of Finished CompositionAccording to Example 4bis

Pharmacokinetic testing was undertaken in vivo in healthy humanvolunteers according to the principles described in FDA's March 2003Guidance for Industry on BIOAVAILABILITY AND BIOEQUIVALENCE STUDIES FORORALLY ADMINISTERED DRUG PRODUCTS—GENERAL CONSIDERATIONS. All testingwas performed in subjects two hours after eating a standardized dinner.Xyrem® doses were administered in two equipotent doses four hours apart.All other tested doses were manufactured as described in Example 4bis.The standardized dinner consisted of 25.5% fat, 19.6% protein, and 54.9%carbohydrates.

The finished composition of Example 4bis given as a 4.5 g once-nightlydose rather than a standard Xyrem® dosing twice (2×2.25 g) nightly 4hours apart, produced a dramatically different pharmacokinetic profilethan Xyrem® as shown in FIG. 22 . As summarized below (Tables 6a and6b), 4.5 g nighttime doses of finished composition of the inventionequivalent to twice-nightly doses of Xyrem® (2×2.25 g) provided somewhatless total exposure to sodium oxybate with a later median Tmax than theinitial Xyrem® dose. The relative bioavailability was about 88%.Composition according to the invention avoids the high second-dose peakconcentration of Xyrem® and therefore does not exhibit the substantialbetween-dose fluctuations in concentration, while achieving a comparablemean C8 h.

TABLE 6a Pharmacokinetic Parameters of finished composition of Example4bis vs. Xyrem ® Mean Mean Mean Median C_(max) AUC_(inf) AUC_(8h)T_(max) Mean C_(8h) (μg/mL) (h*μg/mL) (h*μg/mL) (hour) (μg/mL) (% CV) (%CV) (% CV) (min-max) (% CV) Finished 43.47 (49) 188.96 179.69   2(0.5-7) 6.85 (118) composition (57) (57) of Example 4bis 4.5 g Xyrem ®1^(st) dose: 214.32 202.78 1^(st) dose: 9.24 (127) 2 × 2.25 g 33.41 (41)(48) (46) 1.0 (0.5-2) 2^(nd) dose: 2^(nd) dose: 65.91 (40) 4.5(4.33-6.5)

TABLE 6b Mean plasma concentration of gamma-hydroxybutyrate(microgram/mL) versus time of finished composition of Example 4bis andXyrem ® Finished composition Xyrem ® Time Example 4bis 4.5 g (2 × 2.25g) (hour) (2 h after meal) (N = 15) (N = 15) 0 0.00 0.00 0.5 23.80 27.441 33.26 28.97 1.5 35.60 26.12 2 35.57 21.11 2.5 33.81 13.93 3 30.9610.25 3.5 28.73 6.92 4 26.06 42.32 4.5 23.27 57.33 5 18.68 52.27 5.516.67 43.55 6 15.55 35.20 6.5 13.07 27.44 7 11.75 19.36 7.5 9.20 13.88 86.85 9.24 10 1.94 2.64 12 NC NC NC: Not Calculated

The 4.5 g dose achieved a mean C8 h equal to about 6.85 microgram/mLwhich represents approximately 74.1% of the C8 h obtained for Xyrem®dosed 2×2.25 g. The ratio of AUC8 h to AUCinf was about 0.89.

Example 7. In Vitro and In Vivo Pharmacokinetic Study of a ComparativeFormulation

A formulation having an in vitro dissolution profile comparable to theformulation reported in FIG. 3 of U.S. Pat. No. 8,193,211 was preparedto confirm the in vitro/in vivo correlations reported herein. Tables7a-7c provide the qualitative and quantitative compositions of the MRmicroparticles, and mixtures of IR and MR microparticles. The physicalstructure of the microparticles showing the qualitative and quantitativecomposition of the IR and MR microparticles is depicted in FIGS. 23A and23B, respectively.

Briefly, sodium oxybate immediate release (IR) microparticles wereprepared according to Example 1bis. Sodium oxybate modified release (MR)microparticles were prepared in two steps:

Step 1: 106.7 g of water insoluble polymer Ethylcellulose (Ethocel™ 20Premium), 10.7 g of polyvinylpyrrolidone (Plasdone™ K30 from ISP), 10.7g of castor oil (from Olvea) and 5.3 g of Polyoxyl 40 HydrogenatedCastor Oil (Kolliphor RH40 from BASF), were dissolved in a mixture of828.0 g of acetone, 552.0 g of isopropanol and 153.3 g of water. Thesolution was sprayed entirely on 400.0 g of immediate releasemicroparticles of sodium oxybate prepared above in a fluid bed spraycoater apparatus Glatt G.P.C.G.1.1 with inlet temperature 57° C.,spraying rate around 14.5 g per min and atomization pressure 2.5 bar.Microparticles with volume mean diameter of about 310 microns wereobtained.

Step 2: 15.0 g of Methacrylic acid copolymer Type C (Eudragit™ L100-55from Evonik), 30.0 g of Methacrylic acid copolymer Type B (Eudragit™S100 from Evonik), 67.5 g of Hydrogenated cottonseed oil (Lubritab™),were dissolved in 1012.5 g of isopropanol at 78° C. The solution wassprayed entirely on 450.0 g of the above prepared microparticles in afluid bed spray coater apparatus with an inlet temperature 47° C.,spraying rate around 10.5 g per min and atomization pressure 1.3 bar. MRmicroparticles were dried for two hours with inlet temperature set to56° C. MR Microparticles with volume mean diameter of 335 microns wereobtained.

The finished composition, which contains a 60:40 mixture of MR and IRmicroparticles calculated based on their sodium oxybate content, wasprepared as follows: 326.69 g of the above IR microparticles, 735.04 gof the above MR microparticles, 23.74 g of malic acid (D/L malic acid),5.54 g of xanthan gum (Xantural™ 75 from Kelco), 5.54 g of colloidalsilicon dioxide (Aerosil™ 200 from Degussa) and 11.08 g of magnesiumstearate were mixed. Individual samples of 8.40 g (corresponding to a4.5 g dose of sodium oxybate with 40% of the dose as immediate-releasefraction and 60% of the dose as modified release fraction) were weighed.

TABLE 7a Composition of MR Microparticles Quantity per ComponentFunction 2.25 g dose (g) IR Microparticles Core of MR 2.786Microparticles Ethylcellulose 20 Coating excipient 0.743 Povidone K30Coating excipient 0.074 Polyoxyl 40 Hydrogenated Coating excipient 0.037Castor Oil Castor oil Coating excipient 0.074 Hydrogenated Vegetable OilCoating excipient 0.557 Methacrylic acid Copolymer Coating excipient0.124 Type C Methacrylic acid Copolymer Coating excipient 0.248 Type BEthyl alcohol Solvent Eliminated during processing Acetone SolventEliminated during processing Water Solvent Eliminated during processingIsopropyl alcohol Solvent Eliminated during processing Total 4.644

TABLE 7b Qualitative Composition of Finished Composition Quantity perComponent Function 4.5 g dose (g) MR microparticles Modified releasefraction 5.573 of sodium oxybate IR microparticles Immediate releasefraction 2.477 of sodium oxybate Malic acid Acidifying agent 0.180Xanthan gum Suspending agent 0.042 Colloidal silicon dioxide Glidingagent 0.042 Magnesium stearate Lubricant 0.084 Total 8.398

TABLE 7c Quantitative Composition of Finished Composition Quantity perComponent Function 4.5 g dose (g) Sodium oxybate Drug substance 4.5Microcrystalline cellulose Core 0.836 spheres Povidone K30 der andcoating 0.326 excipient Hydroxypropyl cellulose Top coat 0.248Ethylcellulose 20 Coating excipient 0.892 Polyoxyl 40 HydrogenatedCoating excipient 0.045 Castor Oil Castor oil Coating excipient 0.089Hydrogenated Vegetable Oil Coating excipient 0.669 Methacrylic acidCopolymer Coating excipient 0.149 Type C Methacrylic acid CopolymerCoating excipient 0.297 Type B Malic acid Acidifying agent 0.180 Xanthangum Suspending agent 0.042 Colloidal silicon dioxide Gliding agent 0.042Magnesium stearate Lubricant 0.084 Total 8.398

The dissolution profile obtained for the MR microparticles in twosequential dissolution media (0.1N HCl for 2 hours then phosphate bufferpH 6.8) is shown in FIG. 24 and Table 7d. These data show that thedissolution profile of the MR microparticles produced according thecomparative Example 7 was quite similar to the dissolution profile ofFIG. 3 from U.S. Pat. No. 8,193,211. In particular, the MRmicroparticles according to the comparative Example 7 do not releasemore than 8000 of its sodium oxybate at 3 hours.

TABLE 7d Dissolution profile obtained for the MR microparticles ofExample 7 in two sequential dissolution media (0.1N HCl for 2 hours thenphosphate buffer pH 6.8) Time (hour) Example 7 0 0 1 0 2 1 2.25 5 2.5 443 74 64 89 6 96

The finished composition of Comparative Example 7 was tested in the samepharmacokinetic study than the finished composition of Example 1 and 4.As summarized below (Tables 7e), 4.5 g nighttime dose of finishedcomposition of the comparative Example 7 compared to twice-nightly dosesof Xyrem® (2×2.25 g) provided much less total exposure to sodium oxybatewith a relative bioavailability of 67%.

TABLE 7e Pharmacokinetic Parameters of finished composition ofComparative Example 7 vs. Xyrem ® Mean Mean Median C_(max) AUC_(inf)T_(max) Mean C_(8h) (μg/mL) (h*μg/mL) (hour) (μg/mL) (% CV) (% CV)(min-max) (% CV) Finished 28.99 (45) 143.90 (53) 1.5 (0.5-8)  7.79 (82) composition of Comparative Example 7 4.5 g Xyrem ® 1st dose: 214.32 (48)1st dose: 9.24 (127) 2 × 2.25 g 33.41 (41) 1.0 (0.5-2)  2nd dose: 2nddose: 65.91 (40)   4.5 (4.33-6.5)

TABLE 7f Mean plasma concentration (microgram/mL) ofgamma-hydroxybutyrate versus time of finished composition of ComparativeExample 7 and Xyrem ® Comparative Comparative Example 7 @ Example 7 @Comparative 4.5 g (2 h 6.0 g (2 h Example 7 @ Xyrem ® after meal) aftermeal) 7.5 g (2 h (2 × 2.25 g) Time pooled mean pooled mean after meal)part I (hour) (N = 27) (N = 18) (N = 12) (N = 15) 0 0.00 0.00 0.00 0.000.5 18.84 25.54 31.40 27.44 1 23.93 35.80 46.78 28.97 1.5 24.31 38.5958.29 26.12 2 24.32 40.78 57.47 21.11 2.5 23.10 38.03 52.25 13.93 320.05 35.76 49.00 10.25 3.5 17.47 33.99 45.66 6.92 4 16.48 30.47 40.520.00 4.5 15.44 26.87 37.70 57.33 5 14.10 25.59 36.82 52.27 5.5 12.6024.63 35.93 43.55 6 11.68 23.90 34.47 35.20 6.5 11.45 23.98 31.60 27.447 10.64 20.94 31.89 19.36 7.5 9.35 17.93 29.69 13.88 8 7.79 14.36 25.809.24 10 1.98 3.71 11.00 2.64 12 0.59 0.78 3.63 NC NC: not calculated

The pharmacokinetic profiles of single 6 g and 7.5 g doses of thefinished composition produced according to comparative Example 7 werealso generated. Table 7 g provides data on a single 4.5 g, 6 g and 7.5 gdose, showing effects on Cmax, C8 h, AUC8 h and AUCinf related to dosestrength.

TABLE 7g Pharmacokinetic Parameters of 4.5 g, 6 g, and 7.5 g of finishedcomposition produced according Comparative Example 7 Finished Mean MeanMean Median composition C_(max) AUC_(inf) AUC_(8h) T_(max) Mean C_(8h)Comparative (μg/mL) (h*μg/mL) (h*μg/mL) (min-max) (μg/mL) of Example 7(% CV) (% CV) (% CV) (h) (% CV) (% CV) 4.5 g  28.98 143.90 128.83 1.5 7.79 (45) (53) (55) (0.5-8)   (82)  6 g 45.64 248.24 225.00 2 14.36(35) (47) (47) (0.5-6.5) (77) 7.5 g  63.31 379.83 316.18 1.75 25.80 (33)(54) (48)   (1-4.5) (74)

Example 8. Alternative Formulations Example 8.1: Modified ReleaseFormulation of Gamma-Hydroxybutyrate Comprising Immediate ReleaseMicroparticles of Potassium Salt of Gamma-Hydroxybutyric Acid andModified Release Microparticles of Sodium Salt of Gamma-HydroxybutyricAcid (Sodium Oxybate)

Immediate release (IR) microparticles of potassium salt ofgamma-hydroxybutyric acid may be prepared as follows: 1615.0 g ofpotassium salt of gamma-hydroxybutyric acid and 85.0 g ofpolyvinylpyrrolidone (Povidone K30—Plasdone™ K29/32 from ISP) aresolubilized in 1894.3 g of absolute ethyl alcohol and 1262.9 g of water.The solution is entirely sprayed onto 300 g of microcrystallinecellulose spheres (Cellets™ 127) in a fluid bed spray coater apparatus.

Immediate release (IR) microparticles of sodium salt ofgamma-hydroxybutyric acid were prepared as follows: 1615.0 g of sodiumsalt of gamma-hydroxybutyric acid and 85.0 g of polyvinylpyrrolidone(Povidone K30—Plasdone K29/32 from ISP) were solubilized in 1894.3 g ofabsolute ethyl alcohol and 1262.9 g of water. The solution was entirelysprayed onto 300 g of microcrystalline cellulose spheres (Cellets™ 127from Pharmatrans Sanaq) in a fluid bed spray coater apparatus.

Sodium oxybate modified release (MR) microparticles are prepared asfollows: 22.8 g of methacrylic acid copolymer Type C (Eudragit™L100-55), 45.8 g of methacrylic acid copolymer Type B (Eudragit™ S100),102.9 g of hydrogenated cottonseed oil (Lubritab™), are dissolved in1542.9 g of isopropanol at 78° C. The solution is sprayed entirely onto400.0 g of the sodium oxybate IR microparticles described above in afluid bed spray coater apparatus with an inlet temperature of 48° C.,spraying rate around 11 g per min and atomization pressure of 1.3 bar.MR microparticles are dried for two hours with inlet temperature set to56° C. MR microparticles with mean volume diameter of about 320 micronswere obtained.

The finished formulation, which contains a 50:50 mixture of MR and IRmicroparticles calculated on their gamma-hydroxybutyrate content, may beprepared as follows: 398.51 g of the above IR microparticles, 504.80 gof the above MR microparticles, 16.09 g of D/L malic acid, 6.34 g ofxanthan gum (Xantural™ 75 from Kelco), 9.51 g of carrageenan gum(Viscarin™ PH209 from FMC Biopolymer), 9.51 g of hydroxyethylcellulose(Natrosol™ 250M from Ashland) and 4.75 g of magnesium stearate weremixed. Individual samples of 7.49 g of the mixture (amount equivalent toa 4.5 g dose of sodium oxybate with half of the dose asimmediate-release fraction and half of the dose as modified releasefraction) were weighed.

TABLE 8a Composition of IR Microparticles of gamma-hydroxybutyrate ofexample 8.1 Quantity per Component Function 2.25 g dose (g) Potassiumsalt of Drug substance 2.537 hydroxybutyric acid Microcrystallinecellulose Core 0.471 spheres Povidone K30 Binder and excipient 0.134 indiffusion coating Ethyl alcohol Solvent Eliminated during processingPurified water Solvent Eliminated during processing Total 3.142

TABLE 8b Composition of MR Microparticles of gamma-hydroxybutyrate ofexample 8.1 Quantity per Component Function 2.25 g dose (g) Sodiumoxybate Drug substance 2.25  Povidone K30 Binder 0.118 Microcrystallinecellulose Core 0.419 spheres Hydrogenated Vegetable Oil Coatingexcipient 0.717 Methacrylic acid Copolymer Coating excipient 0.159 TypeC Methacrylic acid Copolymer Coating excipient 0.318 Type B Ethylalcohol Solvent Eliminated during processing Acetone Solvent Eliminatedduring processing Water Solvent Eliminated during processing Isopropylalcohol Solvent Eliminated during processing Total 3.981

TABLE 8c Qualitative Composition of Finished Formulation of Example 8.1Quantity per Component Function 4.5 g dose (g) MR microparticlesModified release fraction of 3.981 sodium oxybate IR microparticlesImmediate release fraction of 3.142 potassium salt of gamma-hydroxybutyric acid Malic acid Acidifying agent 0.127 Xanthan gumSuspending agent 0.050 Hydroxyethylcellulose Suspending agent 0.075Carrageenan gum Suspending agent 0.075 Magnesium stearate Lubricant0.037 Total 7.487

TABLE 8d Quantitative Composition of Finished Formulation of Example 8.1Quantity per Component Function 4.5 g dose (g) Sodium oxybate Drugsubstance 2.25 Potassium salt of gamma- Drug substance 2.537hydroxybutyric acid Microcrystalline cellulose spheres Core 0.890Povidone K30 Binder 0.252 Hydrogenated Vegetable Oil Coating excipient0.717 Methacrylic acid Copolymer Type C Coating excipient 0.159Methacrylic acid Copolymer Type B Coating excipient 0.318 Malic acidAcidifying agent 0.127 Xanthan gum Suspending agent 0.050Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspendingagent 0.075 Magnesium stearate Lubricant 0.037 Total 7.487

Example 8.2: Modified Release Formulation of Gamma-HydroxybutyrateComprising Immediate Release Microparticles of Potassium Salt ofGamma-Hydroxybutyric Acid, Immediate Release Microparticles of MagnesiumSalt of Gamma-Hydroxybutyric Acid, Immediate Release Microparticles ofCalcium Salt of Gamma-Hydroxybutyric Acid and Modified ReleaseMicroparticles of Sodium Salt of Gamma-Hydroxybutyric Acid (SodiumOxybate)

Immediate release (IR) microparticles of potassium salt ofgamma-hydroxybutyric acid are prepared according to example 8.1.

Immediate release (IR) microparticles of magnesium salt ofgamma-hydroxybutyric acid or calcium salt of gamma-hydroxybutyric acidmay be prepared using the same manufacturing process by replacing thepotassium salt of gamma-hydroxybutyric acid by the same weight ofrespectively magnesium salt of gamma-hydroxybutyric acid or calcium saltof gamma-hydroxybutyric acid.

Sodium oxybate modified release (MR) microparticles are preparedaccording to example 8.1.

The finished formulation, which contains a 50:50 mixture of MR and IRmicroparticles calculated on their gamma-hydroxybutyrate content, may beprepared as follows. 132.84 g of the IR microparticles of potassium saltof gamma-hydroxybutyric acid, 215.32 g of the IR microparticles ofmagnesium salt of gamma-hydroxybutyric acid, 230.05 g of the IRmicroparticles of calcium salt of gamma-hydroxybutyric acid, 504.80 g ofthe MR microparticles of sodium oxybate, 23.35 g of D/L malic acid, 6.34g of xanthan gum (Xantural™ 75 from Kelco), 9.51 g of carrageenan gum(Viscarin™ PH209 from FMC Biopolymer), 9.51 g of hydroxyethylcellulose(Natrosol™ 250M from Ashland) and 5.69 g of magnesium stearate weremixed. Individual samples of 8.96 g of the mixture (amount equivalent toa 4.5 g dose of sodium oxybate with half of the dose asimmediate-release fraction and half of the dose as modified releasefraction) were weighed.

TABLE 8e Qualitative Composition of Finished Formulation of Example 8.2Quantity per Component Function 4.5 g dose (g) MR microparticlesModified release fraction of 3.981 sodium oxybate IR microparticlesImmediate release fraction of 4.559 potassium salt of gamma-hydroxybutyric acid + immediate release fraction of magnesium salt ofgamma-hydroxybutyric acid + immediate release fraction of calcium saltof gamma- hydroxybutyric acid Malic acid Acidifying agent 0.184 Xanthangum Suspending agent 0.050 Hydroxyethylcellulose Suspending agent 0.075Carrageenan gum Suspending agent 0.075 Magnesium stearate Lubricant0.045 Total 8.97

TABLE 8f Quantitative Composition of Finished Formulation of Example 8.2Quantity per Component Function 4.5 g dose (g) Sodium oxybate Drugsubstance 2.25 Potassium salt of gamma- Drug substance 0.84hydroxybutyric acid Magnesium salt of gamma- Drug substance 1.37hydroxybutyric acid Calcium salt of gamma- Drug substance 1.46hydroxybutyric acid Microcrystalline cellulose spheres Core  1.102Povidone K30 Binder  0.312 Hydrogenated Vegetable Oil Coating excipient 0.717 Methacrylic acid Copolymer Type C Coating excipient  0.159Methacrylic acid Copolymer Type B Coating excipient  0.318 Malic acidAcidifying agent  0.184 Xanthan gum Suspending agent  0.050Hydroxyethylcellulose Suspending agent  0.075 Carrageenan gum Suspendingagent  0.075 Magnesium stearate Lubricant  0.045 Total 8.96

Example 8.3: Modified Release Formulation of Gamma-HydroxybutyrateComprising Immediate Release Microparticles of Potassium Salt ofGamma-Hydroxybutyric Acid and Modified Release Microparticles of CalciumSalt of Gamma-Hydroxybutyric Acid

Immediate release (TR) microparticles of potassium salt ofgamma-hydroxybutyric acid are prepared according to example 8.1.

Immediate release (TR) microparticles of calcium salt ofgamma-hydroxybutyric acid may be prepared using the manufacturingprocess described in example 8.1 for immediate release (TR)microparticles of potassium salt of gamma-hydroxybutyric acid byreplacing the potassium salt of gamma-hydroxybutyric acid by the sameweight of calcium salt of gamma-hydroxybutyric acid. These Immediaterelease (IR) microparticles of calcium salt of gamma-hydroxybutyric acidare used to manufacture modified release (MR) microparticles of calciumsalt of gamma-hydroxybutyric acid as follows: 22.8 g of methacrylic acidcopolymer Type C (Eudragit™ L100-55), 45.8 g of methacrylic acidcopolymer Type B (Eudragit™ S100), 102.9 g of hydrogenated cottonseedoil (Lubritab™), are dissolved in 1542.9 g of isopropanol at 78° C. Thesolution is sprayed entirely onto 400.0 g of the immediate releasemicroparticles of calcium salt of gamma-hydroxybutyric acid describedabove in a fluid bed spray coater apparatus with an inlet temperature of48° C., spraying rate around 11 g per min and atomization pressure of1.3 bar. MR microparticles are dried for two hours with inlettemperature set to 56° C.

The finished formulation, which contains a 50:50 mixture of MR and IRmicroparticles calculated on their gamma-hydroxybutyrate content, may beprepared as follows: 398.53 g of the IR microparticles of potassium saltof gamma-hydroxybutyric acid, 492.87 g of the MR microparticles ofsodium oxybate, 16.10 g of D/L malic acid, 6.34 g of xanthan gum(Xantural™ 75 from Kelco), 9.51 g of carrageenan gum (Viscarin™ PH209from FMC Biopolymer), 9.51 g of hydroxyethylcellulose (Natrosol™ 250Mfrom Ashland) and 4.69 g of magnesium stearate were mixed. Individualsamples of 7.39 g of the mixture (amount equivalent to a 4.5 g dose ofsodium oxybate with half of the dose as immediate-release fraction andhalf of the dose as modified release fraction) were weighed.

TABLE 8g Qualitative Composition of Finished Formulation of Example 8.3Quantity per Component Function 4.5 g dose (g) MR microparticlesModified release fraction of 3.887 calcium salt of gamma- hydroxybutyricacid IR microparticles Immediate release fraction of 3.143 potassiumsalt of gamma- hydroxybutyric acid Malic acid Acidifying agent 0.127Xanthan gum Suspending agent 0.050 Hydroxyethylcellulose Suspendingagent 0.075 Carrageenan gum Suspending agent 0.075 Magnesium stearateLubricant 0.037 Total 7.39

TABLE 8h Quantitative Composition of Finished Formulation of Example 8.3Quantity per Component Function 4.5 g dose (g) Potassium salt of gamma-Drug substance 2.54 hydroxybutyric acid Calcium salt of gamma- Drugsubstance 2.19 hydroxybutyric acid Microcrystalline cellulose spheresCore 0.880 Povidone K30 Binder 0.249 Hydrogenated Vegetable Oil Coatingexcipient 0.700 Methacrylic acid Copolymer Type C Coating excipient0.155 Methacrylic acid Copolymer Type B Coating excipient 0.311 Malicacid Acidifying agent 0.127 Xanthan gum Suspending agent 0.050Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspendingagent 0.075 Magnesium stearate Lubricant 0.037 Total 7.39

Example 9: Alternative Formulations with Differing Concentrations ofAcidic Agents

Different prototypes were developed to evaluate the effect of acidicagent on the dissolution stability of the formulation dispersed inwater. Experimental data with 0.800, 1.6% and 15% malic acid aredetailed below.

Example 9.1: 1.6% Malic Acid

IR particles were prepared as follows: 1615.0 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.3 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 268 microns were obtained.

MR coated particles were prepared as follows: 39.9 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 80.1 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 180.0 g ofHydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in2700.0 g of isopropanol at 78° C. The solution was sprayed entirely on700.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 49° C., spraying rate around 11.6 gper min and atomization pressure 1.6 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 324 microns were obtained.

The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, was prepared asfollows: 655.1 g of the above IR particles, 936.4 g of the above MRparticles, 26.5 g of Malic acid (D/L malic acid regular from Bartek),11.7 g of xanthan gum (Xantural™ 75 from CP Kelco), 17.6 g ofcarrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 17.6 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 8.2 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 7.1 1 g (corresponding to a 4.5 g dose with half ofthe dose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

FIG. 29 and Table 9a below depict dissolution profiles determined in0.1N HCl using a USP apparatus 2. The dissolution medium was maintainedat 37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm.Single dose units were poured in a container containing 50 mL of tapwater. After 5 and 15 minutes, the suspension was poured in thedissolution vessel containing 840 mL of 0.1N HCl dissolution medium. 10mL of water were used to rinse the container and were added to thedissolution vessel.

TABLE 9a % dissolved 5 min % dissolved 15 min Time (h) reconstitutiontime reconstitution time 0 0 0 0.25 47 48 1 53 52 3 53 53 6 55 54 8 5960 10 74 77 12 87 88 16 96 97 20 97 98

Example 9.2: 0.8% Malic Acid

IR particles were prepared as follows: 1615.0 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.3 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 273 microns were obtained.

MR coated particles were prepared as follows: 39.9 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 80.1 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 180.0 g ofHydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in2700.0 g of isopropanol at 78° C. The solution was sprayed entirely on700.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 47° C., spraying rate around 10.7 gper min and atomization pressure 1.6 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 60° C. Sodium oxybate MRcoated particles with mean diameter of 309 microns were obtained.

The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, was prepared asfollows: 100.0 g of the above IR particles, 142.9 g of the above MRparticles, 2.0 g of Malic acid (D/L malic acid regular from Bartek), 1.2g of xanthan gum (Xantural™ 75 from CP Kelco), 1.2 g of hydrophilicfumed silica (Aerosil™ 200 from Degussa) and 2.5 g of magnesium stearate(from Peter Greven) were mixed in a Roue-Roehn mixer. Individual dosesof 6.93 g (corresponding to a 4.5 g dose with half of the dose asimmediate-release fraction and half of the dose as modified releasefraction) were weighed.

FIG. 30 and Table 9b below depict dissolution profiles determined in0.1N HCl using a USP apparatus 2. The dissolution medium was maintainedat 37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm.Single dose units were poured in a container containing 50 mL of tapwater. After 5 and 15 minutes, the suspension was poured in thedissolution vessel containing 840 mL of 0.1N HCl dissolution medium. 10mL of water were used to rinse the container and were added to thedissolution vessel.

TABLE 9b % dissolved 5 min % dissolved 15 min Time (h) reconstitutiontime reconstitution time 0 0 0 0.25 51 51 1 51 52 3 51 53 6 52 62 8 6086 10 77 96 12 90 98 16 98 98

Example 9.3: 15% Malic Acid

IR particles were prepared as follows: 1615.0 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.3 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 255 microns were obtained.

MR coated particles were prepared as follows: 22.8 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 45.8 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 102.9 g ofHydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1544.8 g of isopropanol at 78° C. The solution was sprayed entirely on400.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 49° C., spraying rate around 12.0 gper min and atomization pressure 1.3 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 298 microns were obtained.

The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, was prepared asfollows: 36.2 g of the above IR particles, 51.8 g of the above MRparticles, 16.1 g of Malic acid (D/L malic acid regular from Bartek),0.7 g of xanthan gum (Xantural™ 75 from CP Kelco), 1.0 g of carrageenangum (Viscarin™ PH209 from FMC Biopolymer), 1.0 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 0.6 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 8.25 g (corresponding to a 4.5 g dose with half ofthe dose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

FIG. 31 and Table 9c below depict dissolution profiles determined in0.1N HCl using a USP apparatus 2. The dissolution medium was maintainedat 37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm.Single dose units were poured in a container containing 50 mL of tapwater. After 5 and 15 minutes, the suspension was poured in thedissolution vessel containing 840 mL of 0.1N HCl dissolution medium. 10mL of water were used to rinse the container and were added to thedissolution vessel.

TABLE 9c % dissolved 5 min % dissolved 15 min Time (h) reconstitutiontime reconstitution time 0 0 0 0.25 48 49 1 51 51 3 51 51 4 51 51 6 5251 8 56 56 10 71 71 12 86 85 16 97 96 20 99 98

Example 10. Alternative Formulations

Suspending agents are present in the formulation to limit microparticlessettling after reconstitution. Without suspending agents, microparticlesstarts settling as soon as shaking stops. In presence of the suspendingagents, full microparticles settling does not occur in less than 1minute. The following data illustrates the good pourability of thesuspension assessed by the high recovery of sodium oxybate content inthe dissolution test:

IR particles were prepared as follows: 1615.0 g of sodium oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.3 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 271 microns were obtained.

MR coated particles were prepared as follows: 39.9 g of methacrylic acidcopolymer type C (Eudragit™ L100-55 from Evonik), 80.1 g of methacrylicacid copolymer type B (Eudragit™ S100 from Evonik), 180.0 g ofhydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in2700.0 g of isopropanol at 78° C. The solution was sprayed entirely on700.0 g of sodium oxybate IR particles in a fluid bed spray coaterapparatus Glatt™ G.P.C.G.1.1 with inlet temperature 48° C., sprayingrate around 11.5 g per min and atomization pressure 1.6 bar. MR coatedparticles were dried for 2 hours with inlet temperature set to 56° C. MRparticles of sodium oxybate with mean diameter of 321 microns wereobtained.

The finished composition, which contains a 50:50 mixture of MR and IRsodium oxybate particles calculated on their sodium oxybate content, wasprepared as follows: 634.0 g of the above IR particles, 907.6 g of theabove MR particles, 25.7 g of malic acid (D/L malic acid regular fromBartek), 11.4 g of xanthan gum (Xantural™ 75 from CP Kelco), 17.1 g ofcarrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 17.1 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 8.1 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 14.20 g (corresponding to a 9 g dose with half ofthe dose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

FIG. 32 and Table 10a below depict dissolution profiles of 9 g dosesdetermined using a USP apparatus 2 in 0.1N HCl. The dissolution mediumwas maintained at 37.0±0.5° C. and the rotating paddle speed was fixedat 75 rpm. Single dose units were poured in a container containing 50 mLof tap water. After 5 minutes, the suspension was poured in thedissolution vessel containing 840 mL of 0.1N HCl dissolution medium. 10mL of water were used to rinse the container and were added to thedissolution vessel. Dissolution profile was determined with and withoutrinsing step.

TABLE 10a Time (h) with rinsing without rinsing 0 0 0 0.25 47 46 1 51 513 53 52 6.0 54 53 8 61 60 10 77 74 12 91 88 16 98 95 20 98 96

Example 11. Alternative Formulations with a Different Ratio of IR and MRFractions

Different prototypes were prepared and evaluated to determine the effectof MI/MR ratio.

Example 11a: 15% IR/85% IR with MR pH*6.5 Microparticles

IR particles were prepared as follows: 1615.0 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1896.2 g of absolute ethyl alcohol and1264.4 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 275 microns were obtained.

MR coated particles were prepared as follows: 22.8 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 45.8 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 102.9 g ofHydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1543.1 g of isopropanol at 78° C. The solution was sprayed entirely on400.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 47° C., spraying rate around 10.8 gper min and atomization pressure 1.3 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 330 microns were obtained.

17.1 g of MR microparticles were mixed with 0.09 g of magnesium stearate(from Peter Greven). The dissolution profile of 4000 mg of the mixturewhich correspond to 2250 mg of sodium oxybate per vessel was determinedin 900 ml of 0.1N HCl and pH 6.8 phosphate buffer (0.05M monobasicpotassium phosphate solution—pH adjusted to 6.8 with 5N NaOH) using theUSP apparatus 2. Dissolution medium temperature was maintained at37.0±0.5° C., and the rotating paddle speed was set at 75 rpm. Therelease profiles are shown in FIG. 33 , Table 11a, and Table 11b.

TABLE 11a Dissolution data-0.1N HCl Time (hour) % dissolved 0 0.0 0.25 11 1 3 2 4 3 6 6 8 24 10 59 12 83 16 95 20 97

TABLE 11b Dissolution data-50 mM phosphate buffer pH 6.8 Time (hour) %dissolved 0 0 0.25 18 0.5 80 0.75 97 1 97 2 97

The qualitative composition of 4.5 g dose units comprising 15% of thedose as IR fraction and 85% of the dose as MR fraction is described inTable 11c.

TABLE 11c Quantity per Component Function 4.5 g dose (g) MRmicroparticles Modified release fraction 6.767 of sodium oxybate IRmicroparticles Immediate release 0.836 fraction of sodium oxybate Malicacid Acidifying agent 0.034 Xanthan gum Suspending agent 0.050Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspendingagent 0.075 Magnesium stearate Lubricant 0.039 Total 7.876

The finished composition, which contains a 85:15 mixture of MR and IRparticles calculated on their sodium oxybate content, may be prepared asfollows: 100.0 g of the above IR particles, 809.5 g of the above MRparticles, 4.0 g of malic acid (D/L malic acid regular from Bartek), 6.0g of xanthan gum (Xantural™ 75 from CP Kelco), 9.0 g of carrageenan gum(Viscarin™ PH209 from FMC Biopolymer), 9.0 g of hydroxyethylcellulose(Natrosol™ 250M from Ashland) and 4.7 g of magnesium stearate (fromPeter Greven) were mixed in a Roue-Roehn mixer. Individual doses of 7.88g (corresponding to a 4.5 g dose with 15% of the dose asimmediate-release fraction and 85% of the dose as modified releasefraction) were weighed.

After reconstitution with 50 ml of tap water and a rinsing volume of 10ml of tap water, the finished composition will display the dissolutionprofiles in FIGS. 34 and 35 and Tables 11d and 11e in 840 ml of 0.1N HCland in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2, at37.0±0.5° C. and the rotating paddle speed at 75 rpm.

TABLE 11d Time (hour) % dissolved 0 0.0 0.25 16 1 16 3 17 4 17 6 20 8 3510 65 12 85 16 96

TABLE 11e Time (hour) % dissolved 0 0 0.25 30 0.5 83 0.75 97 1 98 2 98

Example 11B 30% IR/70% MR with MR pH*6.2 Microparticles

IR particles were prepared as follows: 1615.1 g of sodium oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1903.2 g of absolute ethyl alcohol and1267.1 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 268 microns were obtained.

MR coated particles were prepared as follows: 36.6 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 32.1 g of methacrylicacid copolymer type B (Eudragit™ S 100 from Evonik), 103.0 g ofhydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1543.5 g of isopropanol at 78° C. The solution was sprayed entirely on400.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 48° C., spraying rate around 12.0 gper min and atomization pressure 1.3 bar. MR particles were dried for 2hours with inlet temperature set to 56° C. Sodium oxybate MR coatedparticles with mean diameter of 323 microns were obtained.

17.0 g of sodium oxybate MR particles were mixed with 0.09 g ofmagnesium stearate (from Peter Greven). The dissolution profile of 4050mg of the mixture which correspond to 2280 mg of sodium oxybate pervessel was determined in 900 ml of 0.1N HCl dissolution medium using theUSP apparatus 2. Dissolution medium temperature was maintained at37.0±0.5° C., and the rotating paddle speed was set at 75 rpm. Therelease profile in 0.1N HCl is shown in FIG. 36 and Table 11f.

TABLE 11f Time (hour) % dissolved 0.0 0 0.3 1 1.0 3 3.0 4 4.0 4 6.0 88.0 40 10.0 81 12.0 95 16.0 100 20.0 99

The finished composition, which contains a 70:30 mixture of MR and IRsodium oxybate particles calculated on their sodium oxybate content, wasprepared as follows: 92.1 g of the above IR particles, 306.5 g of theabove MR particles, 7.5 g of malic acid (D/L malic acid regular fromBartek), 2.8 g of xanthan gum (Xantural™ 75 from CP Kelco), 4.1 g ofcarrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 4.1 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 2.0 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 7.62 g (corresponding to a 4.5 g dose with 30% ofthe dose as immediate-release fraction and 70% of the dose as modifiedrelease fraction) were weighed.

FIGS. 37 and 38 and Tables 11 g and 11 h below depict dissolutionprofiles determined using a USP apparatus 2 in 0.1N HCl and pH 6.8phosphate buffer (0.05M monobasic potassium phosphate solution—pHadjusted to 6.8 with 5N NaOH). The dissolution medium was maintained at37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm. Singledose units were poured in a container containing 50 mL of tap water.After 5 minutes, the suspension was poured in the dissolution vesselcontaining 840 mL of dissolution medium. 10 mL of water were used torinse the container and were added to the dissolution vessel.

TABLE 11g Time (hour) % dissolved in 0.1N HCl 0.0 0.0 0.3 29 1.0 31 3.032 4.0 32 6.0 35 8.0 70 10.0 94 12.0 99 16.0 99

TABLE 11h Time (h) % dissolved in pH 6.8 phosphate buffer 0 0 0.25 640.5 87 1 100 2 100 3 102

Example 11c: 65% Ir/35% MR with MR pH 1*6.5 Microparticles

IR particles were prepared as follows: 1615.0 g of sodium oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.3 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 270 microns were obtained.

MR coated particles were prepared as follows: 22.8 g of methacrylic acidcopolymer type C (Eudragit™ L100-55 from Evonik), 45.8 g of methacrylicacid copolymer type B (Eudragit™ S100 from Evonik), 102.9 g ofhydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1543.1 g of isopropanol at 78° C. The solution was sprayed entirely on400.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 47° C., spraying rate around 10.8 gper min and atomization pressure 1.3 bar. MR coated particles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 330 microns were obtained.

Refer to the Example 11a for the dissolution profile of the MRmicroparticles. The qualitative composition of 4.5 g dose unitscomprising 65% of the dose as IR fraction and 35% of the dose as MRfraction is described in Table 11i.

TABLE 11i Quantity per Component Function 4.5 g dose (g) MRmicroparticles Modified release fraction 2.786 of sodium oxybate IRmicroparticles Immediate release 3.622 fraction of sodium oxybate Malicacid Acidifying agent 0.110 Xanthan gum Suspending agent 0.050Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspendingagent 0.075 Magnesium stearate Lubricant 0.034 Total 6.752

The finished composition, which contains a 85:15 mixture of sodiumoxybate MR and IR particles calculated on their sodium oxybate content,may be prepared as follows: 100.0 g of the above IR particles, 76.9 g ofthe above MR coated particles, 3.0 g of Malic acid (D/L malic acidregular from Bartek), 1.4 g of xanthan gum (Xantural™ 75 from CP Kelco),2.1 g of carrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 2.1 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 0.9 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 6.75 g (corresponding to a 4.5 g dose with 65% ofthe dose as immediate-release fraction and 35% of the dose as modifiedrelease fraction) were weighed.

Dissolution profile: After reconstitution with 50 ml tap water andrinsing with 10 ml of tap water, the finished composition will displaythe dissolution profiles in FIGS. 39 and 40 and Tables 11j and 11k in840 ml of 0.1N HCl and in pH 6.8 phosphate buffer (0.05M monobasicpotassium phosphate solution—pH adjusted to 6.8 with 5N NaOH) using aUSP apparatus 2, at 37.0±0.5° C. and the rotating paddle speed at 75rpm.

TABLE 11j Time (hour) % dissolved in 0.1N HCl 0 0.0 0.25 65 1 65 3 66 466 6 67 8 73 10 86 12 94 16 98 20 99

TABLE 11k Time (hour) % dissolved in pH 6.8 phosphate buffer 0 0 0.25 710.5 93 0.75 99 1 99 2 99

Example 12: Alternative Formulations with Ir Fraction Obtained UsingDifferent Manufacturing Processes

Prototype formulations were developed to test the impact of differentmanufacturing processes on the dissolution of the formulations.

Example 12a: IR Portion=Raw Sodium Oxybate

IR particles to serve as cores of the MR coated microparticles wereprepared as follows: 1615.0 g of sodium oxybate and 85.0 g of watersoluble polymer polyvinylpyrrolidone (Povidone—Plasdone™ K30 from ISP)were solubilized in 1894.3 g of absolute ethyl alcohol and 1262.9 g ofwater. The solution was entirely sprayed onto 300 g of microcrystallinecellulose spheres (Cellets™ 127 from Pharmatrans) in a fluid bed spraycoater apparatus GPCG1.1. Sodium oxybate IR particles with mean diameterof 256 microns were obtained.

MR coated particles were prepared as follows: 22.8 g of methacrylic acidcopolymer type C (Eudragit™ L100-55 from Evonik), 45.8 g of methacrylicacid copolymer type B (Eudragit™ S100 from Evonik), 102.9 g ofhydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1542.9 g of isopropanol at 78° C. The solution was sprayed entirely on400.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 48° C., spraying rate around 10 g permin and atomization pressure 1.3 bar. MR particles were dried for 2hours with inlet temperature set to 56° C. Sodium oxybate MR coatedparticles with mean diameter of 308 microns were obtained.

25.2 g of MR microparticles were mixed with 0.26 g of magnesium stearate(from Peter Greven) and 0.13 g of colloidal silicon dioxide (Aerosil™200 from Evonik). The dissolution profile of 4000 mg of the mixturewhich correspond to 2250 mg of sodium oxybate per vessel was determinedin 900 ml of 0.1N HCl dissolution medium using the USP apparatus 2.Dissolution medium temperature was maintained at 37.0±0.5° C., and therotating paddle speed was set at 75 rpm. The release profile in 0.1N HClis shown in FIG. 41 and Table 12a.

TABLE 12a Time (hour) % dissolved 0 0 0.25 1 1 1 3 2 4 3 6 14 8 40 10 6512 78 16 89

The finished composition, which contains a 50:50 mixture of sodiumoxybate MR coated particles and raw sodium oxybate as IR fractioncalculated on their sodium oxybate content, was prepared as follows: 36g of raw sodium oxybate, 63.7 g of the above MR coated particles, 1.8 gof malic acid (D/L malic acid regular from Bartek), 1.6 g of xanthan gum(Xantural™ 75 from CP Kelco), 2.4 g of carrageenan gum (Viscarin™ PH209from FMC Biopolymer), 0.047 g of an apple aroma and 0.3 g of hydrophilicfumed silica (Aerosil 200 from Degussa) were mixed in a Roue-Roehnmixer. Individual doses of 6.66 g (corresponding to a 4.5 g dose withhalf of the dose as raw sodium oxybate as IR fraction and half of thedose as modified release fraction) were weighed.

FIG. 42 and Table 12b below depict dissolution profiles determined usinga USP apparatus 2 in 0.1N HCl. The dissolution medium was maintained at37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm. Singledose units were poured in a container containing 50 mL of tap water.After 5 minutes, the suspension was poured in the dissolution vesselcontaining 840 mL of 0.1N HCl dissolution medium. 10 mL of water wereused to rinse the container and were added to the dissolution vessel.

TABLE 12b Time (hour) % dissolved 0 0 0.25 50 1 52 4 55 6 57 8 70 10 8212 87 16 93

Considering that the 0.1N HCl dissolution profile of the MR coatedparticles is similar to the MR microparticles from examples 1 and 1bis,the dissolution profile in pH 6.8 phosphate buffer of the finishedcomposition is expected to be similar to the profile depicted in FIG. 8, insofar as the MR particles are similar and only the nature of theimmediate-release fraction was changed.

Example 12B: IR=Microparticles Obtained by Extrusion-Spheronization

IR particles were prepared as follows: 97 g of sodium oxybate and 3 g ofwater soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™ K30 fromISP) were mixed with 7.5 g of water. The mixture was extruded through a400-micron mesh and spheronized at 1500 rpm for 1.5 min in anextruder-spheronizer Fuji-Paudal MG-55. After drying for 4 hours at 45°C. in a ventilated oven, microparticles were sieved between 150 micronsand 500 microns.

MR coated particles were prepared as described in Example 14.

The finished composition, which contains a 50:50 mixture of MR and IRsodium oxybate particles calculated on their sodium oxybate content, wasprepared as follows: 67.4 g of the above IR particles obtained byextrusion-spheronization, 115.6 g of the above MR coated particles, 3.3g of malic acid (D/L malic acid regular from Bartek), 0.9 g of xanthangum (Xantural™ 75 from CP Kelco), 0.9 g of hydrophilic fumed silica(Aerosil 200 from Degussa) and 1.9 g of magnesium stearate (from PeterGreven) were mixed in a Roue-Roehn mixer. Individual doses of 6.54 g(corresponding to a 4.5 g dose with half of the dose asimmediate-release fraction and half of the dose as modified releasefraction) were weighed.

FIG. 43 and Table 12c below depict dissolution profiles determined usinga USP apparatus 2 in 0.1N HCl. The dissolution medium was maintained at37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm. Singledose units were poured in a container containing 50 mL of tap water.After 5 minutes, the suspension was poured in the dissolution vesselcontaining 840 mL of 0.1N HCl dissolution medium. 10 mL of water wereused to rinse the container and were added to the dissolution vessel.

TABLE 12c Time (hour) % dissolved in 0.1N HCl 0 0 0.25 51 1 53 4 54 6 548 56 10 65 12 79 16 92Based on the dissolution profile of the MR coated particles in pH 6.8phosphate buffer, finished compositions are expected to have thedissolution profile in pH 6.8 phosphate buffer given in Table 12d andFIG. 44 .

TABLE 12d Time (h) % dissolved in pH 6.8 phosphate buffer 0 0 0.25 550.50 97 1 101 1.5 102 2 101 3 101

Example 13. Alternative Formulation without Binder

IR particles were prepared as follows: 1700.0 g of Sodium Oxybate aresolubilized in 1899.4 g of absolute ethyl alcohol and 1261.3 g of water.The solution is entirely sprayed onto 300 g of microcrystallinecellulose spheres (Cellets 127 from Pharmatrans) in a fluid bed spraycoater apparatus GPCG1.1. Sodium oxybate IR particles with mean diameterof 244 microns are obtained.

MR coated particles were prepared as follows: 17.1 g of methacrylic acidcopolymer type C (Eudragit L100-55 from Evonik), 34.3 g of methacrylicacid copolymer type B (Eudragit S100 from Evonik), and 77.1 g ofhydrogenated cottonseed oil (Lubritab from JRS), are dissolved in 1157.9g of isopropanol at 78° C. The solution is sprayed entirely on 300.0 gof IR particles prepared above in a fluid bed spray coater apparatusGlatt G.P.C.G.1.1 with inlet temperature 48° C., spraying rate around10.7 g per min and atomization pressure 1.3 bar. MR microparticles weredried for 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 289 microns are obtained.

25.3 g of MR coated microparticles were mixed with 0.12 g of magnesiumstearate (from Peter Greven). The dissolution profile of 4000 mg of themixture which correspond to 2368 mg of sodium oxybate per vessel wasdetermined in 900 ml of 0.1N HCl and pH 6.8 phosphate buffer (0.05Mmonobasic potassium phosphate solution with pH adjusted to 6.8 with 5NNaOH) using the USP apparatus 2. Dissolution medium temperature wasmaintained at 37.0±+0.5° C., and the rotating paddle speed was set at 75rpm. The release profiles are shown below in FIG. 45 and Tables 13a and13b.

TABLE 13a Dissolution data-0.1N HCl Time (h) % dissolved 0 0 0.25 0 1 03 1 4 3 6 29 8 50 10 69 12 82 16 97 20 102

TABLE 13b Dissolution data-50 mM pH 6.8 phosphate buffer Time (h) %dissolved 0 0 0.25 5 1 102 3 106

The qualitative composition of 4.5 g dose units comprising 50% of thedose as IR fraction and 50% of the dose as MR fraction is described inTable 13c.

TABLE 13c Quantity per Component Function 4.5 g dose (g) MRmicroparticles Modified release fraction 3.841 of sodium oxybate IRmicroparticles Immediate release 2.647 fraction of sodium oxybate Malicacid Acidifying agent 0.113 Xanthan gum Suspending agent 0.050Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspendingagent 0.075 Magnesium stearate Lubricant 0.034 Total 6.835

After reconstitution with 50 ml of tap water and rinsing with 10 ml oftap water, the finished composition is expected to provide the followingdissolution profiles in FIGS. 46 and 47 and Tables 13d and 13e in 840 mlof 0.1N HCl and pH6.8 phosphate buffer (0.05M monobasic potassiumphosphate solution with pH adjusted to 6.8 with 5N NaOH) using a USPapparatus 2, at 37.0±0.5° C. and the rotating paddle speed at 75 rpm.

TABLE 13d Time (h) % dissolved in 0.1N HCl 0.0 0 0.3 50 1.0 50 3.0 504.0 52 6.0 64 8.0 75 10.0 84 12.0 91 16.0 98 20.0 101

TABLE 13e Time (h) % dissolved in pH 6.8 buffer 0 0 0.25 53 1.0 101 3103

Example 14. MR Particles with Larger Core Size (160 Microns)

Different prototypes were also developed to evaluate the impact of thecore size on the dissolution of the formulation.

IR particles were prepared as follows: 1615.0 g of sodium oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.3 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 100 from Pharmatrans)(D[4,3]=160 microns) in a fluid bed spray coater apparatus GPCG1.1.Sodium oxybate IR particles with mean diameter of 310 microns wereobtained.

MR coated particles were prepared as follows: 25.7 g of methacrylic acidcopolymer type C (Eudragit™ L100-55 from Evonik), 51.5 g of methacrylicacid copolymer type B (Eudragit™ S100 from Evonik), 115.7 g ofhydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1735.7 g of isopropanol at 78° C. The solution was sprayed entirely on450.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 47° C., spraying rate around 9.6 gper min and atomization pressure 1.6 bar. MR particles were dried for 2hours with inlet temperature set to 56° C. Sodium oxybate MR coatedparticles with mean diameter of 370 microns were obtained.

49.3 g of sodium oxybate MR particles were mixed with 0.52 g ofmagnesium stearate (from Peter Greven) and 0.26 g of colloidal silicondioxide (Aerosil™ 200 from Evonik). The dissolution profile of 4000 mgof the mixture which correspond to 2250 mg of sodium oxybate per vesselwas determined using the USP apparatus 2 in 900 ml of 0.1N HCl mediumand pH 6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH). Dissolution mediumtemperature was maintained at 37.0±0.5° C., and the rotating paddlespeed was set at 100 rpm. The release profile in 0.1N HCl and pH 6.8phosphate buffer is shown below in FIG. 48 and Tables 14a and 14b.

TABLE 14a Dissolution data-0.1N HCl Time (h) % dissolved 0 0 0.25 0 1 13 2 6 3 8 7 10 18 12 37 16 75

TABLE 14b Dissolution data-50 mM pH 6.8 phosphate buffer Time (h) %dissolved 0 0 0.25 9 0.5 95 1 101 3 101

The qualitative composition of 4.5 g dose units comprising 50% of thedose as IR fraction and 50% of the dose as MR fraction is described inTable 14c.

TABLE 14c Quantity per Component Function 4.5 g dose (g) MRmicroparticles Modified release fraction 2.786 of sodium oxybate IRmicroparticles Immediate release 3.981 fraction of sodium oxybate Malicacid Acidifying agent 0.113 Xanthan gum Suspending agent 0.050Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspendingagent 0.075 Magnesium stearate Lubricant 0.037 Total 7.115

After reconstitution with 50 ml of tap water and rinsing with 10 ml oftap water, the finished composition is expected to provide thedissolution profiles in FIGS. 49 and 50 and Table 14d and 14e in 840 mlof 0.1N HCl and in pH6.8 phosphate buffer (0.05M monobasic potassiumphosphate solution with pH adjusted to 6.8 with 5N NaOH) using a USPapparatus 2, at 37.0±0.5° C. and the rotating paddle speed at 75 rpm.

TABLE 14d Time (hour) % dissolved in 0.1N HCl 0 0 0.25 50 1 51 4 51 6 528 53 10 59 12 69 16 87

TABLE 14e Time (hour) % dissolved in pH 6.8 buffer 0 0 0.25 55 1 101 3101

Example 15. MR Microparticles with Different Ratios of Lubritab™ andEudragit™

Different prototypes were developed to evaluate the effect of the ratiobetween Lubritab™ and Eudragit™ on the formulation.

Example 15a: 30% Lubritab™; Cellets™ 127; Coating Level=35%

IR particles were prepared as follows: 1615.0 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.3 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 100 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 272 microns were obtained.

MR coated particles were prepared as follows: 50.2 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 100.6 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 64.6 g ofHydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1943.5 g of isopropanol at 78° C. The solution was sprayed entirely on400.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 48° C., spraying rate around 11.0 gper min and atomization pressure 1.3 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 403 microns were obtained.

17.9 g of sodium oxybate MR microparticles were mixed with 0.1 g ofmagnesium stearate (from Peter Greven). The dissolution profile of 4308mg of the mixture which corresponds to 2250 mg of sodium oxybate pervessel was determined using the USP apparatus 2 in 900 ml of 0.1N HClmedium. Dissolution medium temperature was maintained at 37.0±0.5° C.,and the rotating paddle speed was set at 75 rpm. The release profile isshown in FIG. 51 and Table 15a.

TABLE 15a Time (h) % dissolved in 0.1N HCl 0 0 0.25 3 1 5 3 69 4 96 6101 8 102 10 102

Alternative MR coated particles of sodium oxybate were preparedaccording to the above manufacturing protocol with the coating leveladjusted to 50% instead of 35%. The dissolution profile of thealternative sodium oxybate MR particles was determined using the sameprotocol as above. The 0.1N HCl dissolution profile is shown in FIG. 52and Table 15b.

TABLE 15b Time (h) % dissolved 0 0 0.25 1 1 1 3 36 4 67 6 95 8 98 10 98

The finished composition, which contains a 50:50 mixture of MR and IRsodium oxybate particles calculated on their sodium oxybate content, wasprepared as follows: 153.3 g of the above IR microparticles, 235.8 g ofthe above sodium oxybate MR microparticles with a coating level of 30%,6.2 g of malic acid (D/L malic acid regular from Bartek), 2.7 g ofxanthan gum (Xantural™ 75 from CP Kelco), 4.1 g of carrageenan gum(Viscarin™ PH109 from FMC Biopolymer), 4.1 g of hydroxyethylcellulose(Natrosol™ 250M from Ashland) and 2.0 g of magnesium stearate (fromPeter Greven) were mixed in a Roue-Roehn mixer. Individual doses of 7.42g (corresponding to a 4.5 g dose with half of the dose asimmediate-release fraction and half of the dose as modified releasefraction) were weighed.

FIG. 53 and Table 15c below depict dissolution profiles determined usinga USP apparatus 2 in 0.1N HCl. The dissolution medium was maintained at37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm. Singledose units were poured in a container containing 50 mL of tap water.After 5 minutes, the suspension was poured in the dissolution vesselcontaining 840 mL of 0.1N HCl dissolution medium. 10 mL of water wereused to rinse the container and were added to the dissolution vessel.

TABLE 15c Time (hour) % dissolved 0 0 0.25 45 1 52 2 92 3 94 4 97 6 97 897 10 96

Example 15B: Celphere™ CP203 as Neutral Cores and Coating Level=35%

IR particles were prepared as follows: 665.0 g of Sodium Oxybate and35.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 781.2 g of absolute ethyl alcohol and521.6 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Celphere™ CP203 from AsahiKasei—mean diameter D[4,3]=250 microns) in a fluid bed spray coaterapparatus GPCG1.1. Sodium oxybate IR particles with mean diameter of 398microns were obtained.

MR coated particles were prepared as follows: 37.6 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 75.4 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 48.5 g ofHydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1458.0 g of isopropanol at 78° C. The solution was sprayed entirely on300.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 48° C., spraying rate around 11.7 gper min and atomization pressure 1.6 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 491 microns were obtained.

17.0 g of MR microparticles were mixed with 0.08 g of magnesium stearate(from Peter Greven). The dissolution profile of 5210 mg of the mixturewhich corresponds to 2250 mg of sodium oxybate per vessel was determinedusing the USP apparatus 2 in 900 ml of 0.1N HCl medium and in pH 6.8phosphate buffer (0.05M monobasic potassium phosphate solution—pHadjusted to 6.8 with 5N NaOH). Dissolution medium temperature wasmaintained at 37.0±0.5° C., and the rotating paddle speed was set at 75rpm. The release profile is shown in FIG. 54 and Tables 15d and 15e.

TABLE 15d Dissolution data-0.1N HCl Time (hour) % dissolved 0 0 0.25 3 13 3 45 4 77 6 96 8 98 10 98

TABLE 15e Dissolution data-50 mM pH 6.8 phosphate buffer Time (h) %dissolved 0 0 0.25 1 0.5 22 0.75 87 1 98 2 97

The qualitative composition of 4.5 g dose units comprising 50% of thedose as IR fraction and 50% of the dose as MR fraction is described inTable 15f.

TABLE 15f Quantity per Component Function 4.5 g dose (g) MRmicroparticles Modified release fraction 5.205 of sodium oxybate IRmicroparticles Immediate release fraction 3.383 of sodium oxybate Malicacid Acidifying agent 0.113 Xanthan gum Suspending agent 0.050Hydroxyethylcellulo Suspending agent 0.075 Carrageenan gum Suspendingagent 0.075 Magnesium stearate Lubricant 0.045 Total 8.946

After reconstitution, the finished composition is expected to exhibitthe dissolution profiles in FIGS. 55 and 56 and Tables 15 g and 15 h in0.1N HCl and in pH6.8 phosphate buffer (0.05M monobasic potassiumphosphate solution with pH adjusted to 6.8 with 5N NaOH) using a USPapparatus 2, at 37.0±0.5° C. and the rotating paddle speed at 75 rpm.

TABLE 15g Time (h) % dissolved in 0.1N HCl 0 0 0.25 51 1 51 3 73 4 88 698 8 99 10 99

TABLE 15h Time (h) % dissolved in pH 6.8 buffer 0 0 0.25 50 0.5 61 0.7593 1 99 2 99

Example 15c: 40% Lubritab™ (Coating Level=40%)

IR pellets were prepared as follows: 1615.0 g of Sodium Oxybate and 85.0g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™ K30from ISP) were solubilized in 1903.2 g of absolute ethyl alcohol and1267.1 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 268 microns were obtained.

MR coated particles were prepared as follows: 40.6 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 80.1 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 80.5 g ofHydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1799.4 g of isopropanol at 78° C. The solution was sprayed entirely on300.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 48° C., spraying rate around 10.5 gper min and atomization pressure 1.3 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 348 microns were obtained.

20.0 g of MR coated particles were mixed with 0.1 g of magnesiumstearate (from Peter Greven). The dissolution profile of 4700 mg of themixture which corresponds to 2250 mg of sodium oxybate per vessel wasdetermined using the USP apparatus 2 in 900 ml of 0.1N HCl medium.Dissolution medium temperature was maintained at 37.0±0.5° C., and therotating paddle speed was set at 75 rpm. The release profile is shown inFIG. 57 and Table 15i.

TABLE 15i Time (h) % dissolved in 0.1N HCl 0 0 0.25 0 1 0 3 1 4 8 6 52 884 10 95 12 97 16 98

The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, was prepared asfollows: 156.0 g of the above IR particles, 260.0 g of the above MRcoated particles, 6.3 g of malic acid (D/L malic acid regular fromBartek), 2.8 g of xanthan gum (Xantural™ 75 from CP Kelco), 4.2 g ofcarrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 4.2 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 2.2 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 7.78 g (corresponding to a 4.5 g dose with half ofthe dose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

FIGS. 58 and 59 and Tables 15j and 15k below depict dissolution profilesdetermined in 0.1N HCl and pH 6.8 buffer (0.05M monobasic potassiumphosphate solution with pH adjusted to 6.8 with 5N NaOH) using a USPapparatus 2. The dissolution medium was maintained at 37.0±0.5° C. andthe rotating paddle speed was fixed at 75 rpm. Single dose units werepoured in a container containing 50 mL of tap water. After 5 minutes,the suspension was poured in the dissolution vessel containing 840 mL of0.1N HCl dissolution medium. 10 mL of water were used to rinse thecontainer and were added to the dissolution vessel.

TABLE 15j Time (h) % dissolved in 0.1N HCl 0 0 0.25 48 1 52 3 52 4 62 689 8 96 10 97 12 98 16 98 20 97

TABLE 15k Time (h) % dissolved in pH 6.8 buffer 0 0 0.25 49 0.5 85 1 912 96 3 104

Example 15D: 70% Lubritab™ (Coating Level 25%)

IR particles were prepared as follows: 1615.1 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.4 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 272 microns were obtained.

MR coated particles were prepared as follows: 13.3 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 26.8 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 93.3 g ofHydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1200.3 g of isopropanol at 78° C. The solution was sprayed entirely on400.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 48° C., spraying rate around 10.6 gper min and atomization pressure 1.3 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 313 microns were obtained.

17.0 g of MR coated particles were mixed with 0.06 g of magnesiumstearate (from Peter Greven). The dissolution profile of 3750 mg of themixture which corresponds to 2250 mg of sodium oxybate per vessel wasdetermined using the USP apparatus 2 in 900 ml of 0.1N HCl medium andpH6.8 phosphate buffer (0.05M monobasic potassium phosphate solution—pHadjusted to 6.8 with 5N NaOH). Dissolution medium temperature wasmaintained at 37.0±0.5° C., and the rotating paddle speed was set at 75rpm. The release profile is shown in FIG. 60 and Tables 15l and 15m.

TABLE 15l Dissolution profile in 0.1N HCl Time (h) % dissolved 0 0.00.25 5 1 4 3 5 4 5 6 8 8 33 10 78 12 98 16 103

TABLE 15M Dissolution profile in 50 mM pH 6.8 phosphate buffer Time (h)% dissolved 0 0.0 0.25 1 0.5 45 1 97 2 108 3 114

The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, was prepared asfollows: 153.3 g of the above IR particles, 204.3 g of the above MRcoated particles, 6.2 g of Malic acid (D/L malic acid regular fromBartek), 2.7 g of xanthan gum (Xantural™ 75 from CP Kelco), 4.1 g ofcarrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 4.1 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 1.9 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 6.85 g (corresponding to a 4.5 g dose with half ofthe dose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

FIGS. 61 and Table 15n depict the dissolution profiles determined in0.1N HCl using a USP apparatus 2. The dissolution medium was maintainedat 37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm.Single dose units were poured in a container containing 50 mL of tapwater. After 5 minutes, the suspension was poured in the dissolutionvessel containing 840 mL of 0.1N HCl dissolution medium. 10 mL of waterwere used to rinse the container and were added to the dissolutionvessel.

TABLE 15n Time (h) % dissolved 0 0 0.25 48 1 52 3 52 4 52 6 55 8 76 1095 12 100 16 100 20 100

-   -   Based on the dissolution profile of the MR coated particles in        pH 6.8 phosphate buffer, single dose units are expected to have        the dissolution profile in pH6.8 buffer shown in FIG. 62 and in        Table 15o.

TABLE 15o % dissolved in Time (h) pH 6.8 buffer 0 0.0 0.25 51 0.5 72 199 2 104 3 107

Example 16. Evaluation of Different Hydrophobic Compounds in the Coating

Prototypes with different hydrophobic coatings were prepared andevaluated to determine the effect of coating type on the dissolution ofthe formulations.

Example 16a: Glyceryl Dibehenate (Compritol™ ATO888)

IR particles were prepared as follows: 1615.0 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1903.2 g of absolute ethyl alcohol and1267.1 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 268 microns were obtained.

MR coated particles were prepared as follows: 22.9 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 45.8 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 102.9 g of glyceryldibehenate (Compritol™ ATO 888 from Gattefossé), were dissolved in1371.8 g of isopropanol at 78° C. The solution was sprayed entirely on400.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 48° C., spraying rate around 11.7 gper min and atomization pressure 1.6 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 322 microns were obtained.

17.0 g of MR coated particles were mixed with 0.1 g of magnesiumstearate (from Peter Greven). The dissolution profile of 4000 mg of themixture which corresponds to 2250 mg of sodium oxybate per vessel wasdetermined using the USP apparatus 2 in 900 ml of 0.1N HCl medium and inpH 6.8 phosphate buffer (0.05M monobasic potassium phosphate solution—pHadjusted to 6.8 with 5N NaOH). Dissolution medium temperature wasmaintained at 37.0±0.5° C., and the rotating paddle speed was set at 75rpm. The release profile is shown in FIG. 63 and Tables 16a and 16b.

TABLE 16a Dissolution profile-0.1N HCl Time (h) % dissolved 0 0 0.25 0 11 3 3 4 6 6 31 8 67 10 90 12 98 16 100

TABLE 16b Dissolution profile-50 mM pH 6.8 phosphate buffer Time (h) %dissolved 0 0 0.25 1 1 102 3 105

The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, was prepared asfollows: 181.1 g of the above IR particles, 258.7 g of the above MRcoated particles, 7.3 g of Malic acid (D/L malic acid regular fromBartek), 3.3 g of xanthan gum (Xantural™ 75 from CP Kelco), 4.9 g ofcarrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 4.9 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 2.3 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 7.12 g (corresponding to a 4.5 g dose with half ofthe dose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

FIGS. 64 and Table 16c depict dissolution profiles determined in 0.1NHCl using a USP apparatus 2. The dissolution medium was maintained at37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm. Singledose units were poured in a container containing 50 mL of tap water.After 5 minutes, the suspension was poured in the dissolution vesselcontaining 840 mL of 0.1N HCl dissolution medium. 10 mL of water wereused to rinse the container and were added to the dissolution vessel.

TABLE 16c % dissolved Time (hour) in 0.1N HCl 0 0 0.25 46 1 50 3 51 4 566 78 8 92 10 96 12 97 16 96

Based on the dissolution profile of the MR microparticles alone in pH6.8 phosphate buffer, single dose units are expected to have thedissolution profile at pH6.8 shown in FIG. 65 and in Table 16d.

TABLE 16d % dissolved in Time (hour) pH 6.8 buffer 0 0 0.25 50 1 101 3102

Example 16B: 60% Candelilla Wax with Coating Level of 20%

IR particles were prepared as follows: 1615.1 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.4 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 255 microns were obtained.

MR coated particles were prepared as follows: 13.3 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 26.7 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 60.0 g of candelillawax (Kahlwax™ 2039L from Brenntag), were dissolved in 902.2 g ofisopropanol at 78° C. The solution was sprayed entirely on 400.0 g of IRparticles in a fluid bed spray coater apparatus Glatt™ G.P.C.G.1.1 withinlet temperature 48° C., spraying rate around 12.8 g per min andatomization pressure 1.3 bar. MR microparticles were dried for 2 hourswith inlet temperature set to 56° C. Sodium oxybate MR coated particleswith mean diameter of 289 microns were obtained.

21.2 g of MR microparticles were mixed with 0.11 g of magnesium stearate(from Peter Greven). The dissolution profile of 4000 mg of the mixturewhich corresponds to 2570 mg of sodium oxybate per vessel was determinedusing the USP apparatus 2 in 900 ml of 0.1N HCl medium and in pH 6.8phosphate buffer (0.05M monobasic potassium phosphate solution—pHadjusted to 6.8 with 5N NaOH). Dissolution medium temperature wasmaintained at 37.0±0.5° C., and the rotating paddle speed was set at 75rpm. The release profiles are shown below in FIG. 66 and Tables 16e and16f.

TABLE 16e Dissolution profile-0.1N HCl Time (h) % dissolved 0 0 0.25 0 10 3 0 4 1 6 2 8 2 10 2 12 2 16 3 20 4

TABLE 16f Dissolution profile-50 mM pH 6.8 phosphate buffer Time (h) %dissolved 0 0 0.25 0 0.5 10 0.75 62 1 89 2 101

The qualitative composition of 4.5 g dose units comprising 50% of thedose as IR fraction and 50% of the dose as MR fraction is described inTable 16 g.

TABLE 16g Quantity per Component Function 4.5 g dose (g) MRmicroparticles Modified release fraction 3.483 of sodium oxybate IRmicroparticles Immediate release 2.786 fraction of sodium oxybate Malicacid Acidifying agent 0.113 Xanthan gum Suspending agent 0.050Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspendingagent 0.075 Magnesium stearate Lubricant 0.033 Total 6.615The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, may be prepared asfollows: 200.0 g of the above IR particles, 250.0 g of the above MRcoated particles, 8.1 g of Malic acid (D/L malic acid regular fromBartek), 3.6 g of xanthan gum (Xantural™ 75 from CP Kelco), 5.4 g ofcarrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 5.4 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 2.4 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 6.61 g (corresponding to a 4.5 g dose with half ofthe dose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed. After reconstitution, the finishedcomposition is expected to provide the dissolution profiles in FIGS. 67and 68 and Tables 16 h and 16i in 0.1N HCl and in pH6.8 phosphate buffer(0.05M monobasic potassium phosphate solution with pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2, at 37.0±0.5° C. and the rotatingpaddle speed at 75 rpm.

TABLE 16h % dissolved in Time (hour) 0.1N HCl 0 0 0.25 50 1 50 3 50 4 506 51 8 51 10 51 12 51 16 52 20 52

TABLE 16i % dissolved in Time (hour) pH 6.8 buffer 0 0 0.25 50 0.5 550.75 81 1 94 2 100

Example 16c: 40% Candelilla Wax (Coating Level=20%)

IR particles were prepared as follows: 1615.1 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.4 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 270 microns were obtained.

MR coated particles were prepared as follows: 20.0 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 40.0 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 40.0 g of candelillawax (Kahlwax™ 2039L from Brenntag), were dissolved in 904.0 g ofisopropanol at 78° C. The solution was sprayed entirely on 400.0 g of IRparticles in a fluid bed spray coater apparatus Glatt™ G.P.C.G.1.1 withinlet temperature 48° C., spraying rate around 10.9 g per min andatomization pressure 1.3 bar. MR microparticles were dried for 2 hourswith inlet temperature set to 56° C. Sodium oxybate MR coated particleswith mean diameter of 302 microns were obtained.

17.0 g of MR microparticles were mixed with 0.08 g of magnesium stearate(from Peter Greven). The dissolution profile of 3500 mg of the mixturewhich corresponds to 2250 mg of sodium oxybate per vessel was determinedusing the USP apparatus 2 in 900 ml of 0.1N HCl medium and pH 6.8phosphate buffer (0.05M monobasic potassium phosphate solution—pHadjusted to 6.8 with 5N NaOH) is given in FIG. 69 and Tables 16j and16k. Dissolution medium temperature was maintained at 37.0±0.5° C., andthe rotating paddle speed was set at 75 rpm.

TABLE 16j Dissolution profile in 0.1N HCl Time (h) % dissolved 0 0 0.250 1 3 3 6 4 8 6 9 8 15 10 37 12 70 16 97 20 100

TABLE 16k Dissolution profile in 50 mM pH 6.8 phosphate buffer Time (h)% dissolved 0 0 0.25 24 0.5 86 0.75 99 1 100 2 100

The qualitative composition of 4.5 g dose units comprising 50% of thedose as IR fraction and 5000 of the dose as MR fraction is described inTable 16l.

TABLE 16l Quantity per Component Function 4.5 g dose (g) MRmicroparticles Modified release fraction 3.483 of sodium oxybate IRmicroparticles Immediate release 2.786 fraction of sodium oxybate Malicacid Acidifying agent 0.113 Xanthan gum Suspending agent 0.050Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspendingagent 0.075 Magnesium stearate Lubricant 0.033 Total 6.615

The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, was prepared asfollows: 122.7 g of the above IR particles, 153.2 g of the above MRcoated particles, 5.0 g of malic acid (D/L malic acid regular fromBartek), 2.2 g of xanthan gum (Xantural™ 75 from CP Kelco), 3.3 g ofcarrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 3.3 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 1.5 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 6.62 g (corresponding to a 4.5 g dose with half ofthe dose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

FIGS. 70 and Table 16m depict dissolution profiles determined using aUSP apparatus 2 in 0.1N HCl. The dissolution medium was maintained at37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm. Singledose units were poured in a container containing 50 mL of tap water.After 5 minutes, the suspension was poured in the dissolution vesselcontaining 840 mL of 0.1N HCl dissolution medium. 10 mL of water wereused to rinse the container and were added to the dissolution vessel.

TABLE 16m % dissolved Time (hour) in 0.1N HCl 0 0 0.25 47 1 51 3 51 4 526 52 8 55 10 72 12 89 16 97

Based on the dissolution profile of the MR coated particles in pH6.8phosphate buffer, 4.5 g single dose units of the finished compositionsare expected to provide the dissolution profile in pH 6.8 phosphatebuffer shown in FIG. 71 and in Table 16n.

TABLE 16n Time (h) % dissolved in pH 6.8 buffer 0 0 0.25 62 0.5 93 0.7599 1 100 2 100

Example 16D—60% Cetyl Alcohol (Kolliwax™ Ca)

IR particles were prepared as follows: 1615.1 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1898.7 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 272 microns were obtained.

MR coated particles were prepared as follows: 22.8 g of methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 45.8 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 102.9 g of cetylalcohol (Kolliwax™ CA from BASF), were dissolved in 1472.5 g ofisopropanol and 77.7 g of water at room temperature. The solution wassprayed entirely on 400.0 g of IR particles in a fluid bed spray coaterapparatus Glatt™ G.P.C.G.1.1 with inlet temperature 48° C., sprayingrate around 14.5 g per min and atomization pressure 2.5 bar. Sodiumoxybate MR coated particles with mean diameter of 315 microns wereobtained.

16.4 g of MR microparticles were mixed with 0.08 g of magnesium stearate(from Peter Greven). The dissolution profile of 4000 mg of the mixturewhich corresponds to 2250 mg of sodium oxybate per vessel was determinedusing the USP apparatus 2 in 900 ml of 0.1N HCl medium is given in FIG.72 and Table 16o. Dissolution medium temperature was maintained at37.0±0.5° C., and the rotating paddle speed was set at 75 rpm.

TABLE 16o Time (h) % dissolved in 0.1N HCl 0 0 0.25 13 1 84 3 103 4 1036 103 8 103 10 104 12 104 16 103 20 102

Example 17. Effect of Eudragit™ Selection in the Coating of the MRMicroparticles

Further prototypes were developed and evaluate to determine the effectof the Eudragit™ selected on the dissolution of the MR microparticles.

Example 17a 100% Eudragit™ S100

IR particles were prepared as follows: 1615.0 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.3 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 285 microns were obtained.

Sodium oxybate IR seal-coated particles were prepared by coating the IRparticles described above with a seal-coat layer: 170.0 g ofhydroxypropylcellulose (Klucel™ EF Pharm from Hercules) were solubilizedin 4080.0 g of acetone. The solution was entirely sprayed onto 1530.0 gof the above IR particles in a fluid bed spray coater apparatus. Sodiumoxybate IR particles with volume mean diameter of about 298 microns wereobtained.

MR coated particles were prepared as follows: 100.0 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 150.0 g ofHydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in2250.0 g of isopropanol at 78° C. The solution was sprayed entirely on750.0 g of the above IR particles in a fluid bed spray coater apparatusGlatt™ G.P.C.G.1.1 with inlet temperature 48° C., spraying rate around12.0 g per min and atomization pressure 1.6 bar. MR microparticles weredried for 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 307 microns were obtained.

The dissolution profile of 2100 mg of the mixture which corresponds to1253 mg of sodium oxybate per vessel was determined using the USPapparatus 2 in 500 ml of 0.1N HCl medium is reported in FIG. 73 andTable 17a. Dissolution medium temperature was maintained at 37.0±0.5°C., and the rotating paddle speed was set at 100 rpm.

TABLE 17a Time (h) % dissolved 0 0 0.25 0 1 1 3 3 4 4 6 9 8 30 10 60 1281 16 92

The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, was prepared asfollows: 425.0 g of the above IR seal-coated particles, 510.0 g of theabove MR coated particles, 30.9 g of malic acid (D/L malic acid regularfrom Bartek), 4.9 g of xanthan gum (Xantural™ 180 from CP Kelco), 4.9 gof Aerosil™ 200 (amorphous anhydrous colloidal silicon dioxide fromEvonik) and 9.9 g of magnesium stearate (from Peter Greven) were mixedin a Roue-Roehn mixer. Individual doses of 7.18 g (corresponding to a4.5 g dose with half of the dose as immediate-release fraction and halfof the dose as modified release fraction) were weighed.

FIG. 74 and Table 17b below depict dissolution profiles determined usinga USP apparatus 2 in 0.1N HCl. The dissolution medium was maintained at37.0±0.5° C. and the rotating paddle speed was fixed at 100 rpm. Singledose units were poured in a container containing 50 mL of tap water.After 5 minutes, the suspension was poured in the dissolution vesselcontaining 840 mL of 0.1N HCl dissolution medium. 10 mL of water wereused to rinse the container and were added to the dissolution vessel.

TABLE 17b Time (hour) % dissolved in 0.1N HCl 0 0 0.25 50 1 50 3 50 4 516 55 8 67 10 84 12 91 16 94

FIG. 75 and Table 17c depict the dissolution profile determined using aUSP apparatus 2 in phosphate buffer pH 6.8 (0.05M monobasic potassiumphosphate solution—pH adjusted to 6.8 with 5N NaOH). The dissolutionmedium was maintained at 37.0±0.5° C. and the rotating paddle speed wasfixed at 100 rpm. Single dose units were poured in a containercontaining 50 mL of tap water. After 5 minutes, the suspension waspoured in the dissolution vessel containing 840 mL of pH 6.8 dissolutionmedium. 10 mL of water were used to rinse the container and were addedto the dissolution vessel.

TABLE 17c Time (hour) % dissolved 0 0 0.25 50 1 51 3 54 4 56 6 93 8 9910 100 12 100 16 97

Example 17B 100% Eudragit™ L100-55

IR particles were prepared as follows: 1615.0 g of Sodium Oxybate and85.1 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1896.2 g of absolute ethyl alcohol and1264.4 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 275 microns were obtained.

MR coated particles were prepared as follows: 68.7 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 102.9 g ofhydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1543.2 g of isopropanol at 78° C. The solution was sprayed entirely on400.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 46° C., spraying rate around 12.7 gper min and atomization pressure 1.3 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 328 microns were obtained.

17.0 g of MR microparticles were mixed with 0.09 g of magnesium stearate(from Peter Greven). The dissolution profile in of 4000 mg of themixture which corresponds to 2250 mg of sodium oxybate per vessel wasdetermined using the USP apparatus 2 in 900 ml of 0.1N HCl medium and inpH 6.8 phosphate buffer (0.05M monobasic potassium phosphate solution—pHadjusted to 6.8 with 5N NaOH) is given in FIG. 76 and Tables 17d and17e. Dissolution medium temperature was maintained at 37.0±0.5° C., andthe rotating paddle speed was set at 100 rpm.

TABLE 17d Dissolution profile in 0.1N HCl Time (h) % dissolved 0 0 0.250 1 2 3 3 4 6 6 53 8 95 10 99 12 99 16 99 20 99

TABLE 17e Dissolution profile in 50 mM pH 6.8 phosphate buffer Time (h)% dissolved 0 0 0.25 21 0.5 99 0.75 103 1 103 2 103

The finished composition, which contains a 50:50 mixture of MR and TRparticles calculated on their sodium oxybate content, was prepared asfollows: 153.3 g of the above IR particles, 219.0 g of the above MRcoated particles, 6.2 g of malic acid (D/L malic acid regular fromBartek), 2.8 g of xanthan gum (Xantural™ 75 from CP Kelco), 4.1 g ofcarrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 4.1 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 1.9 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 7.12 g (corresponding to a 4.5 g dose with half ofthe dose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

FIG. 77 and Table 17f depict dissolution profiles determined using a USPapparatus 2 in 0.1N HCL. The dissolution medium was maintained at37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm. Singledose units were poured in a container containing 50 mL of tap water.After 5 minutes, the suspension was poured in the dissolution vesselcontaining 840 mL of 0.1N HCl dissolution medium. 10 mL of water wereused to rinse the container and were added to the dissolution vessel.

TABLE 17f Time (hour) % dissolved 0 0 0.25 46 1 51 3 52 4 59 6 94 8 9810 98 12 98 16 98

Based on the dissolution profile of the MR coated particles in pH6.8phosphate buffer, 4.5 g single dose units of the finished compositionsare expected to provide the dissolution profile in pH 6.8 phosphatebuffer in FIG. 78 and Table 17 g.

TABLE 17g Time (h) % dissolved in pH 6.8 buffer 0 0 0.25 61 0.5 99 0.75101 1 101 2 101

Example 17c Mixture Eudragit™ L100-S100 (50-50)

IR particles were prepared as follows: 1615.0 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1903.2 g of absolute ethyl alcohol and1267.1 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 268 microns were obtained.

MR coated particles were prepared as follows: 34.3 g of Methacrylic acidcopolymer Type A (Eudragit™ L100 from Evonik), 34.3 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 102.9 g ofHydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1543.0 g of isopropanol at 78° C. The solution was sprayed entirely on400.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 48° C., spraying rate around 11.8 gper min and atomization pressure 1.3 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 316 microns were obtained.

24.0 g of MR microparticles were mixed with 0.12 g of magnesium stearate(from Peter Greven). The dissolution profile of 4050 mg of the mixturewhich corresponds to 2280 mg of sodium oxybate per vessel was determinedusing the USP apparatus 2 in 900 ml of 0.1N HCl medium and in pH 6.8phosphate buffer (0.05M monobasic potassium phosphate solution—pHadjusted to 6.8 with 5N NaOH) is given in FIG. 79 and Tables 17 h and17i. Dissolution medium temperature was maintained at 37.0±0.5° C., andthe rotating paddle speed was set at 100 rpm.

TABLE 17h Dissolution profile in 0.1N HCl Time (h) % dissolved 0 0 0.250 1 2 3 2 4 3 6 7 8 31 10 62 12 83 16 98 20 100

TABLE 17i Dissolution profile in 50 mM pH 6.8 phosphate buffer Time (h)% dissolved 0 0 0.25 2 0.5 5 0.75 13 1 47 2 101

The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, was prepared asfollows: 223.0 g of the above IR particles, 318.4 g of the above MRcoated particles, 11.2 g of malic acid (D/L malic acid regular fromBartek), 4.0 g of xanthan gum (Xantural™ 75 from CP Kelco), 6.0 g ofcarrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 6.0 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 2.9 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 7.14 g (corresponding to a 4.5 g dose with half ofthe dose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

FIG. 80 and Table 17j depict dissolution profiles determined using a USPapparatus 2 in 0.1N HCl. The dissolution medium was maintained at37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm. Singledose units were poured in a container containing 50 mL of tap water.After 5 minutes, the suspension was poured in the dissolution vesselcontaining 840 mL of 0.1N HCl dissolution medium. 10 mL of water wereused to rinse the container and were added to the dissolution vessel.

TABLE 17j Time (hour) % dissolved 0 0 0.25 47 1 51 3 51 6 59 8 80 10 9212 96 16 97

Based on the dissolution profile of the MR coated particles in pH6.8phosphate buffer, 4.5 g single dose units of the finished compositionare expected to have the dissolution profile in pH 6.8 phosphate buffergiven in FIG. 81 and Table 17k.

TABLE 17k Time (h) % dissolved in pH 6.8 buffer 0 0 0.25 51 0.5 53 0.7556 1 73 2 100

Example 18: In Vivo Pharmacokinetic Study of Finished CompositionAccording to Example 1 (Dose Escalating Study)

Pharmacokinetic testing was undertaken in vivo in healthy humanvolunteers. Pharmacokinetic parameters were normalized by the dose. Toassess the dose-proportionality, log-transformed dose-normalized PKparameters were pairwise compared according to the statisticalmethodology described in FDA's 2013 Draft Guidance entitledBIOEQUIVALENCE STUDIES WITH PHARMACOKINETIC ENDPOINTS FOR DRUGSSUBMITTED UNDER AN ANDA (2013). All testing was performed in subjectstwo hours after eating a standardized dinner. A test product withfinished composition of Example 1 and manufactured at larger scale wasadministered in sequential ascending doses, 4.5 g, 7.5 g and 9 g, oneweek apart. The tested samples were manufactured as described in Table1c for 4.5 g and quantities were homothetically adjusted for the otherstrengths. The dissolution profiles of the MR portions of the testproduct are presented in FIGS. 86 and 87 . The dissolution profiles ofthe test product are presented in FIGS. 88 and 89 . The individualconcentrations of gamma-hydroxybutyrate and derived PK parameters aresummarized below (Tables 18a and 18b) and in FIG. 90 .

TABLE 18a Pharmacokinetic Parameters of 4.5 g, 7.5 g, and 9 g FinishedMean Mean Mean Median composition C_(max) AUC_(inf) AUC_(8h) T_(max)Mean C_(8h) of test (μg/mL) (μg/mL*h) (μg/mL*h) (hour) (μg/mL) product(% CV) (% CV) (% CV) (min-max) (% CV) 4.5 g 42.9 (37) 191 (50) 174 (55)1.71 4.76 (105) (0.333-4) 7.5 g 72.0 (32) 357 (48) 320 (46) 1.5  19.7(101) (0.333-7) 9.0 g 84.5 (34) 443 (46) 379 (41) 2 (0.5-4) 25.5 (97) 

AUC and C_(max) values increased more than dose-proportionally withincreasing doses of gamma-hydroxybutyrate formulated as the testproduct.

TABLE 18b Mean plasma concentration of gamma-hydroxybutyrate(microgram/mL) versus time of finished composition of test product Testproduct 4.5 g Test product 7.5 g Test product 9 g (2 h after meal) (2 hafter meal) (2 h after meal) Time (hr) (N = 20) (N = 20) (N = 12) 0 0.000.00 0.00 0.167 12.5 17.7 9.34 0.333 23.4 39.0 32.7 0.5 28.1 48.4 47.5 134.7 59.8 60.9 1.5 36.7 63.8 71.6 2 35.7 61.6 79.3 2.5 34.7 56.0 64.9 329.8 50.1 65.3 3.5 26.9 46.0 60.0 4 23.5 40.9 60.8 4.5 20.1 36.6 48.8 517.3 32.7 45.3 5.5 15.4 30.8 41.3 6 13.4 28.7 37.6 7 9.66 24.7 30.5 84.76 19.7 25.5 10 0.727 6.97 13.0 12 0.211 1.35 5.13 14 NC 0.392 0.820NC: Not Calculated

Table 18c compares the pharmacokinetic parameters AUCinf and C8 hobtained for 4.5 g of the test product to the same parameters calculated2×2.25 g, i.e. 4.5 g total dose of Xyrem®.

TABLE 18c Comparison to 4.5 g divided dose of Xyrem ® Ratio (%) Ratio(%) Mean C_(8h) Mean AUC_(inf) C_(8h) composition to AUC_(inf)composition to (μg/mL) C_(8h) Xyrem ® (μg/mL*h) AUC_(inf) Xyrem ®Xyrem ® 9.24 NA 214 NA 2 × 2.25 g * Test product 4.76 52% 191 89% 4.5g * data from the pilot PK study of example 3

Table 18d compares the pharmacokinetic parameters AUCinf and C8 hobtained for 7.5 g of the test product to the same parameters calculated2×3.75 g, i.e. 7.5 g total dose of Xyrem®.

TABLE 18d Comparison to 7.5 g divided dose of Xyrem ® Ratio (%) Ratio(%) Mean C_(8h) Mean AUC_(inf) C_(8h) composition to AUC_(inf)composition to (μg/mL) C_(8h) Xyrem ® (μg/mL*h) AUC_(inf) Xyrem ®Xyrem ® 24.1 NA 432 NA 2 × 3.75 g (extrapolation from 2 × 4.5 g *) Testproduct 19.7 82% 357 83% 7.5 g * based on data from NDA #21-196

Table 18e compares the pharmacokinetic parameters AUC_(inf) and C_(8h)obtained for 7.5 g and 9 g of the test product to the same parameterscalculated for 2×4.5 g, i.e. 9 g total dose of Xyrem®.

TABLE 18e Comparison to 9 g divided dose of Xyrem ® Ratio (%) Ratio (%)Mean C_(8h) Mean AUC_(inf) C_(8h) composition to AUC_(inf) compositionto (μg/mL) C_(8h) Xyrem ® (μg/mL*h) AUC_(inf) Xyrem ® Xyrem ® 28.9 NA518 NA 2 × 4.5 g * Test product 19.7 68% 357 69% 7.5 g Test product 25.588% 443 86% 9 g * data from NDA #21-196

For the finished composition administered at 4.5 g, mean C_(6h), meanC_(7h) are greater than, and mean C_(10h) are less than, the mean C_(4h)of the dose of Xyrem®. In addition, the ratio C_(3h)/C_(max) (Xyrem®) is1.03. The ratio C_(4h)/C_(max) (Xyrem®) is 0.81. The ratioC_(4.5h)/C_(max) (Xyrem®) is 0.69.

For the finished composition administered at 7.5 g, mean C_(6h), meanC_(7h) are greater than, and mean C_(10h) are less than, the mean C_(4h)of the dose of Xyrem®. In addition, the ratio C_(3h)/C_(max) (Xyrem®) is0.77. The ratio C_(4h)/C_(max) (Xyrem®) is 0.63. The ratioC_(4.5h)/C_(max) (Xyrem®) is 0.57.

For the finished composition administered at 9 g, mean C_(6h), meanC_(7h) are greater than, and mean C_(10h) are less than, the mean C_(4h)of the dose of Xyrem®. In addition, the ratio C_(3h)/C_(max) (Xyrem®) is0.84. The ratio C_(4h)/C_(max) (Xyrem®) is 0.78. The ratioC_(4.5h)/C_(max) (Xyrem®) is 0.63.

For the finished composition administered at 7.5 g compared to Xyrem® at2×4.5 g, i.e. total dose of 9 g, the ratio C_(3h)/C_(max) (Xyrem®) is0.65. The ratio C_(4h)/C_(max) (Xyrem®) is 0.53. The ratioC_(4.5h)/C_(max) (Xyrem®) is 0.47.

Example 19: Clinical Study of Composition According to Example 1

The efficacy of the composition according to Example 1 (FT218) for thetreatment of cataplexy or excessive daytime sleepiness (EDS) in adultswith narcolepsy was established based on a double-blind, randomized,placebo-controlled, two arm multi-center study to assess the efficacyand safety of a once nightly administration of FT218 in patients withnarcolepsy. In some instances, FT218 may be referred to as LUMRYZ.

A total of 212 subjects were randomized to the active or placebo arm ina 1:1 ratio. The study was divided into four sequential study periodsand incorporates dose titration to stabilized dose administration ofFT218 (4.5 g, 6 g, 7.5 g, and 9 g). There was a three-week screeningperiod, a 13-week treatment period including up-titration over a periodof eight weeks and five weeks of stable dosing at 9 g/night, and aone-week follow-up period. The up-titration included dosing at 4.5 g forweek 1, dosing at 6 g for weeks 2-3, dosing at 7.5 g for weeks 4-8, anddosing at 9 g for weeks 9-13. Stable dosing at 9 g/night means thedosing did not change once the 9 g dose was given. Patients could be onconcomitant stimulant use as long as it was stable for 3 weeks prior tostudy start.

The three co-primary endpoints were the Maintenance of Wakefulness Test(MWT), Clinical Global Impression-Improvement (CGI-I) and mean change inweekly cataplexy attacks. The Epworth Sleepiness Scale (ESS) was asecondary endpoint in the study. Other measures include the number ofarousals determined by PSG, the Visual analogue scale (VAS), number ofhypnogogic hallucination, and number of sleep paralysis. The results ofthese endpoints may be found in Tables 19a-19i.

The Maintenance of Wakefulness Test measures latency to sleep onset (inminutes) averaged over five sessions at 2-hour intervals followingnocturnal polysomnography. For each test session, patients wereinstructed to remain awake for as long as possible during 30-minute testsessions, and sleep latency was determined as the number of minutespatients could remain awake. The overall score was the mean sleeplatency for the 5 sessions. The Clinical Global Impression-Improvementwas evaluated on a 7-point scale, centered at No Change and ranging fromVery Much Worse to Very Much Improved. Patients were rated by evaluatorswho based their assessments on the severity of narcolepsy at Baseline.

ESS total score is defined as the sum of the eight item scores, or thesum of the available item scores and imputed item scores (as the averageof the available ones) if one or two item scores are missing. If morethan two of the eight item scores have missing results, ESS score willbe assigned as missing. Higher total scores indicate a greater tendencyto sleepiness. Baseline is defined as the last assessment at Visit 2.Arousals are the number of transient arousals on the nocturnalpolysomnogram (PSG) as defined by the American Academy of Sleep MedicineScoring Guidelines for the PSG. Visual analogue scale (VAS) was part ofthe Sleep and Symptom Daily Diary with two categories, i.e. sleepquality and refreshing nature of sleep. Each category is a 1-100 scalewith 1 indicating “did not sleep” or “not refreshed”, and 100 indicating“slept very well” or “refreshed”, respectively. VAS is the mean of theresponses to the quality of sleep question averaged over the past 14days preceding the test day. Number of Hypnogogic Hallucination (HH) wascollected via the Sleep and Symptom Daily Diary. Averaged quantity of HHand/or their log transformed data, whichever gives minimal AIC was usedin this MMRM analysis. Number of Sleep Paralysis (SP) is collected viathe Sleep and Symptom Daily Diary. Averaged quantity of SP and/or theirlog transformed data, whichever gives minimal AIC will be used in thisMMRM analysis. Averaged quantity was calculated as the number of eventsaveraged over the 14 days preceding the test day. If a week had lessthan 3 days of Diary entries, data (both the score and count of days)collected of that week would be considered invalid and excluded fromanalyses. Baseline is calculated as the mean of the past 14 dayspreceding Visit 2.

Demographic and mean Baseline characteristics were similar for the FT218and placebo groups. A total of 76% were NT1 patients and 24% were NT2patients. Mean age was 31.2 years and 68% was female. Approximately 63%patients were on concomitant stimulant use. The mean MWT at Baseline was5 minutes for the FT218 group and 4.7 minutes for the placebo group. Themean number of cataplexy attacks per week at Baseline was 18.9 in theFT218 group and 19.8 in the placebo group. For the three co-primaryendpoints, statistically significant improvement was seen on theMaintenance of Wakefulness Test, Clinical Global Impression-Improvementand mean weekly cataplexy attacks for the 6 g (Week 3), 7.5 g (Week 8)and 9 g (Week 13) dose of FT218 compared to the placebo group (seeTables 19a, 19b, and 19c). Results (MWT and CGI-I) were consistentbetween NT1 and NT2 patients as well as patients on stimulants comparedto those not on stimulants.

TABLE 19a Change from Baseline in the Maintenance of Wakefulness Test(in minutes) Treatment Group Change from Difference from Dose (N)Baseline (SE) Placebo [95% CI] p-value   6 g  FT218 (87) 8.08 (0.75)4.98 [2.90; 7.05] <0.001 (Week 3) Placebo (88) 3.10 (0.74) 7.5 g  FT218(76) 9.55 (0.86) 6.21 [3.84; 8.58] <0.001 (Week 8) Placebo (78) 3.34(0.84)   9 g  FT218 (68) 10.82 (0.96)  6.13 [3.52, 8.75] <0.001 (Week13) Placebo (78) 4.69 (0.92) Mean (SD) MWT at Baseline was 4.99 (3.15)minutes for the FT218 group and 4.73 (2.58) minutes for the placebogroup.

TABLE 19b Proportion of Patients with a Very Much or Much ImprovedClinical Global Impression-Improvement Percentage of RespondersTreatment (Much or Very Odds Ratio Dose Group (N) Much Improved) [95%CI] p-value   6 g  FT218 (87) 40.1 10.29 <0.001 (Week 3) [3.93; 26.92]Placebo (87) 6.1 — — 7.5 g  FT218 (75) 62.6 5.67 [2.82; 11.40] <0.001(Week 8) Placebo (81) 22.8 — —   9 g  FT218 (69) 72.0 5.56 [2.76; 11.23]<0.001 (Week 13) Placebo (79) 31.6 — —

TABLE 19c Change from Baseline in the Mean Cataplexy Attacks Per WeekDifference from Treatment Change from Placebo Dose Group (N) Baseline(SE) [95% CI] p-value   6 g  FT218 (55) −7.42 (0.79) −4.83 <0.001 (Week3) [−7.03; −2.62] Placebo (62) −2.59 (0.79) — — 7.5 g  FT218 (66) −9.98(0.88) −6.23 <0.001 (Week 8) [−8.74; −3.80] Placebo (69) −3.71 (0.88) ——   9 g  FT218 (73) −11.51 (0.96)  −6.65 <0.001 (Week 13) [−9.32; −3.98]Placebo (72)  −4.86 (0.945) — — Mean (SD) number of cataplexy attacksper week at Baseline was 18.93 (8.70) in the FT218 group and 19.82(8.87) in the placebo group.

TABLE 19d Change from Baseline in the Mean Disturbed Nocturnal Sleep(DNS) measured by polysomnography (PSG) Difference from Treatment Changefrom Placebo Dose Group (N) Baseline (SE) [95% CI] p-value   6 g  FT218(88) −9.7 (1.82) −11.00 <0.001 (Week 3) [−16.07; −5.93] Placebo (88)1.31 (1.81) — — 7.5 g  FT218 (76) −15.00 (2.32) −17.70 [−24.12; <0.001(Week 8) −11.28] Placebo (79) 2.70 (2.28) — —   9 g  FT218 (69) −20.54(2.19) −22.63 [−28.60; <0.001 (Week 13) −16.66] Placebo (78) 2.09 (2.09)— — Mean (SD) disturbed nocturnal sleep (DNS) measured by PSG atBaseline was 60.1 (23.37) in the FT218 group and 60.3 (21.77) in theplacebo group.

TABLE 19e Change from Baseline in the Epworth Sleepiness Scale (ESS)Difference Treatment Change from from Placebo Dose Group (N) Baseline(SE) [95% CI] p-value   6 g  FT218 (93) −3.48 (0.42) −2.06 [−3.23;<0.001 (Week 3) −0.89] Placebo (91) −1.42 (0.42) — — 7.5 g  FT218 (83)−5.34 (0.54) −3.16 [−4.67; <0.001 (Week 8) 1.64] Placebo (85) −2.18(0.54) — —   9 g  FT218 (73) −6.52 (0.58) −3.86 [−5.47; <0.001 (Week 13)−2.26] Placebo (80) −2.66 (0.57) — — Mean (SD) Epworth Sleepiness Scale(ESS) at Baseline was 16.6 (3.84) in the FT218 group and 17.5 (4.04) inthe placebo group.

TABLE 19f Change from Baseline in the Number of Arousals Determined byPSG Difference Treatment Change from from Placebo Dose Group (N)Baseline (SE) [95% CI] p-value   6 g  FT218 (88) −31.32 (3.45) −11.29[−20.89; <0.001 (Week 3) −1.69] Placebo (88) −20.03 (3.44) — — 7.5 g FT218 (76) −39.16 (3.83) −19.41 [−30.00; <0.001 (Week 8) −8.82] Placebo(79) −19.75 (3.76) — —   9 g  FT218 (69) −39.39 (4.15) −23.68 [−35.01;<0.001 (Week 13) −12.35] Placebo (78) −15.71 (3.96) — — Mean (SD) numberof arousals determined by PSG at Baseline was 81.8 (43.68) in the FT218group and 77.2 (38.13) in the placebo group.

TABLE 19g Change from Baseline in the Visual Analogue Scale (VAS) forSleep Quality Difference Treatment Change from from Placebo Dose Group(N) Baseline (SE) [95% CI] p-value   6 g  FT218 (97) 11.94 (1.11)  6.95[3.84; 10.06] <0.001 (Week 3) Placebo (93) 4.99 (1.12) — — 7.5 g  FT218(83) 18.83 (1.40)  9.87 [5.98; 13.76] <0.001 (Week 8) Placebo (85) 8.96(1.39) — —   9 g  FT218 (73) 21.40 (1.66)  10.41 <0.001 (Week 13) [5.82;15.01] Placebo (79) 10.98 (1.63)  — — Mean (SD) visual analogue scalefor sleep quality at Baseline was 53.78 (20.85) in the FT218 group and55.94 (22.62) in the placebo group.

TABLE 19h Change from Baseline in the Number of Hypnogogic Hallucination(HH) Difference Treatment Change from from Placebo Dose Group (N)Baseline (SE) [95% CI] p-value   6 g  FT218 (73) −0.12 (0.02) −0.014[−0.08; 0.05]  <0.001 (Week 3) Placebo (72) −0.11 (0.02) — — 7.5 g FT218 (62) −0.21 (0.03) −0.08 [−0.17; 0.01] <0.001 (Week 8) Placebo(65) −0.13 (0.03) — —   9 g  FT218 (54) −0.24 (0.04) −0.07 [−0.17; 0.04]<0.001 (Week 13) Placebo (62) −0.17 (0.04) — — Mean (SD) number ofhypnogogic hallucinations at Baseline was 0.45 (0.40) in the FT218 groupand 0.52 (0.41) in the placebo group.

TABLE 19i Change from Baseline in the Number of Sleep Paralysis (SP)Difference Treatment Change from from Placebo Dose Group (N) Baseline(SE) [95% CI] p-value   6 g  FT218 (73) −0.28 (0.06) −0.19 [−0.37;<0.001 (Week 3) −0.01] Placebo (72) −0.09 (0.06) — — 7.5 g  FT218 (62)−0.42 (0.07) −0.22 [−0.41; <0.001 (Week 8) −0.04] Placebo (65) −0.20(0.07) — —   9 g  FT218 (54) −0.43 (0.08) −0.23 [−0.45; <0.001 (Week 13)−0.014] Placebo (62) −0.19 (0.08) — — Mean (SD) number of sleepparalysis at Baseline was 0.67 (0.95) in the FT218 group and 0.94 (1.38)in the placebo group.

Example 20: Pharmacokinetics of FT218 Embodiment

A pilot study, dose-proportionality study, relative bioavailabilitystudy, and food-effect study were conducted. Individuals eligible forstudy enrollment were men or women (white/non-Hispanic or Latino) 18-65years of age who weighed 60 kg with a body mass index of 18e28 kg/m2 andwere considered healthy by comprehensive clinical assessment (detailedmedical history and complete physical examination). All participants hadnormal supine blood pressure and heart rate, ECG findings, laboratoryparameters, and dietary habits and were nonsmokers (or able to abstainfrom smoking during the clinical inpatient period). Women were requiredto be nonpregnant and nonlactating, and all participants had to useadequate forms of contraception if sexually active. Specific exclusioncriteria across studies included succinic semialdehyde dehydrogenasedeficiency, sleep apnea, suicidal ideation, migraine, symptomatichypotension, asymptomatic postural hypotension, use of renal orhepatic-clearing medication within 30 days of study start, use ofvitamins (such as St. John's wort) within 21 days of study start,positive drug screen result, or alcohol use. All participants providedwritten informed consent for participation, and studies were approved bythe local institutional review board or independent ethics committee.Studies were performed in accordance with the Declaration of Helsinki.

In each of the four studies, at each sampling time point, 4-6 mL ofblood was drawn (via indwelling intravenous catheter or directvenipuncture) in a heparinized tube and centrifuged at 1500 g for 5 minat 4 C within 30 min of blood draw. At least 2 mL of the top layer ofplasma was transferred into 2 prelabeled polypropylene tubes, eachcontaining at least 1000 mL of plasma and frozen at −70° C. (+/−15° C.)within 2 h. Blood samples were sent for analysis to Eurofins/ADMEBioanalyses. Concentrations of GHB in sodium heparinized human plasmawere assayed according to an analytical method validated byEurofins/ADME Bioanalyses. The method involves a liquideliquidextraction followed by LC-MS/MS with a calibration range of 0.2 mg/mL asthe lower limit of quantitation to 150 mg/mL as the upper limit ofquantitation. Quality control principles were applied throughout theperformance of the studies. All study samples were analyzed withanalytical runs that complied with acceptance ranges for the qualitycontrol samples. Frozen quality control samples at 3 times the lowerlimit of quantitation (0.6 mg/mL), 0.5 times the upper limit ofquantitation (75 mg/mL), and 0.8 times the upper limit of quantitation(120 mg/mL) GHB concentration levels were used. The quality controlconcentration levels covered the study sample concentration range of0.204-143 mg/mL. Incurred sample reanalysis was approximately 98%, metthe acceptance criteria, and indicated the robustness of the analyticalmethod. Pharmacokinetic parameters were calculated usingnoncompartmental analysis with Kinetica software or WinNonlin software.

Evaluated pharmacokinetic parameters were estimated from the plasmaconcentration time data for plasma GHB and included C_(max), t_(max),concentration 8 h after administration (C_(8h)), AUC₀₋₈, AUC_(inf), andAUC_(0-t)). AUC was calculated using log-transformed data (logarithmictrapezoid method). In the pilot study, pharmacodynamic effects wereexplored using the Leeds Sleep Evaluation Questionnaire (LSEQ; gettingto sleep, quality of sleep, awake following sleep, behavior followingwakening) and actigraphy (sleep time >8 h).

Safety evaluations included AE reporting, physical examination, andmonitoring of vital signs and clinical laboratory values. It wasprespecified that participants who vomited after study drug intake wereexcluded from the primary analysis.

Statistical analyses were performed using SAS statistical software.Descriptive statistics with no formal statistical analysis were used forsafety parameters, general analysis of pharmacokinetic parameters in allstudies, and LSEQ scores and actigraphy in the pilot study. Variabilityof concentrations of FT218 and twice-nightly SO were compared in termsof SD. Bioequivalence was analyzed using the two 1-sided test procedureon log-transformed data for C_(max), AUC_(0-t), and AUC_(inf) and wasdefined as 90% CIs for ratios of geometric means falling within the80%-125% range. Dose proportionality was assessed using the power modelwith slope estimate and 90% CI for dosenormalized pharmacokinetic data.Sensitivity analyses were performed using ANOVA on log-transformednormalized data.

Pilot Study

The pilot study was a randomized, open-label, crossover study toevaluate the pharmacokinetic properties, safety profile, andtolerability of 3 formulations of FT218 (prototypes 1, 2, and 3)compared with twice-nightly sodium oxybate (SO). Participants wererandomized 1:1:1:1 to a single 4.5-g dose of each formulation of FT218or 4.5 g twice-nightly SO (given as two 2.25-g doses 4 h apart) in 4different sequential orders separated by a washout period of 3 days.

The pilot study included 16 participants (8 men and 8 women), with amean (SD) age of 39.5 (11.9) years. There were no study discontinuationsdue to adverse events (AEs).

In the pilot study, for FT218 treatment, blood samples were collectedfrom all participants before dosing and at 30 min and 1, 1.5, 2, 2.5, 3,3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 10, and 12 h after dosing. Fortwice-nightly SO treatment, the same time points were used for the firstdose (omitting the 2.5-hour collection), with an additional collection20 min after the second dose (at 4 h 20 min).

Each of the 3 FT218 formulations exhibited an extended-release profilewith t_(max) at approximately 2 h, followed by a gradual decline inplasma GHB concentration (Table 20a and FIG. 134 ). C_(max) for the 3FT218 formulations was lower than the global C_(max) of twice-nightly SO(mean [SE] C_(max) was 43 [6] μg/mL for prototype 1, 46 [5] μg/mL forprototype 2, 30 [4] μg/mL for prototype 3, and 66 [7] μg/mL fortwice-nightly SO). Mean (SE) AUC_(inf) was 189 (28) h*mg/mL forprototype 1, 210 (28) h*μg/mL for prototype 2, 153 (22) h*mg/mL forprototype 3, and 214 (27) h*μg/mL for twice-nightly SO. C_(8h) valueswere numerically lower for the 3 FT218 formulations (mean [SE] prototype1, 6.85 [2.1]; prototype 2, 7.40 [1.6]; prototype 3, 8.33 [1.9] μg/mL)relative to twice-nightly SO (mean [SE], 9.24 [3.2] μg/mL).

TABLE 20a Pharmacokinetic properties in the pilot study FT218 4.5 gTwice-Nightly Type 1 Type 2 Type 3 SO 4.5 g Parameter (n = 12) (n = 12z0(n = 12) (n = 12) C_(max), mean 43 (6) 46 (5) 30 (4) 66 (7) (SE), μg/mLAUC_(inf), mean 189 (28) 210 (28) 153 (22) 214 (27) (SE), h*μg/mLC_(8h), mean 6.85 (2.09) 7.40 (1.63) 8.33 (1.93) 9.24 (3.15) (SE), μg/mL

Prototype 2 was selected for further optimization and used in theremainder of the studies because it exhibited pharmacokineticcharacteristics closest to the desired target profile, with higherC_(max) compared with other prototypes and AUC_(inf) comparable to thatof twice-nightly SO. For each LSEQ domain and sleep time >8 h, thereappeared to be no clinically meaningful differences between the FT218prototypes and twice-nightly SO.

Four participants reported a total of 5 Aes. All AEs were mild tomoderate in severity, with no SAEs or AEs leading to studydiscontinuation. AEs were comparable between the 3 prototypes of FT218and twice-nightly SO.

Dose-Proportionality Study

The dose-proportionality study was an open-label, single-dose,3-sequential period study to assess the pharmacokinetic properties,safety profile, and tolerability of single dose FT218 (optimizedprototype selected from the pilot study) 4.5, 7.5, and 9 g, and toestimate dose proportionality. Participants received 3 separate singledoses of FT218 (without titration) in a sequential order of 4.5, 7.5,and 9 g with a minimum 7-day washout period between doses.

The dose-proportionality study included 20 individuals (12 men and 8women), with a mean (SD) age of 45.5 (12.5) years. All participantscompleted the 4.5- and 7.5-g periods of the study, and 12 of 20participants (60.0%) completed the 9-g period. The study was stopped bythe sponsor after a serious AE (SAE) of somnolence in 1 individual(described below) after 12 participants were given the 9-g dose levelwithout titration. One individual was withdrawn owing to a positive drugscreen.

In the dose-proportionality study, blood samples were collected beforedosing; at 10, 20, and 30 min after dosing; and at 1, 1.5, 2, 2.5, 3,3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12, and 14 h after dosing.

At all 3 doses of FT218, mean pharmacokinetic properties exhibitedsimilar overall profiles (Table 20b and FIG. 135 ). The t_(max) wasreached after approximately 1.5-2 h followed by a gradual decline in GHBconcentration. Mean (SD) C_(max) increased with increasing doses ofFT218 (42.9 [15.8] μg/mL at 4.5 g, 72.0 [23.3] μg/mL at 7.5 g, and 84.5[28.6] μg/mL at 9 g). Similarly, mean (SD) AUC_(inf) increased withincreasing doses of FT218 (191 [94.7]h*μg/mL at 4.5 g, 358 [170] h*μg/mLat 7.5 g, and 443 [202] h*μg/mL at 9 g). Mean (SD) C_(8h) also increasedwith increasing doses of FT218 (4.8 [5.01] μg/mL at 4.5 g, 19.7 [19.9]μg/mL at 7.5 g, and 25.5 [24.8] μg/mL at 9 g). Moreover, the variabilityof the concentrations was similar.

TABLE 20b Pharmacokinetic properties in the dose-proportionality studyFT218 4.5 FT218 FT218 Parameter g (n = 20) 7.5 g (n = 20) 9 g (n = 11)T_(max), median 1.71 1.5 2 (range), h (0.33-4) (0.33-7) (0.5-4) C_(max),mean (SD), 42.9 72.0 84.5 μg/mL [CV] (15.8) [37] (23.3) [32] (28.6) [34]AUC_(inf), mean (SD), 191 358 443 h*μg/mL [CV] (94.7) [50] (170) [48](202) [46] AUC₀₋₈, mean (SD), 174 320 379 h*μg/mL [CV] (96.3) [55] (148)[46] (154) [41] C_(8h), mean (SD), 4.76 19.7 25.5 μg/mL [CV] (5.01) [37](19.9) [101] (24.8) [97]

Using the power method, the estimated slope of C_(max) was 1.02 (90% CI,0.76-1.28), indicating dose proportionality, and the estimated slope ofAUC_(inf) was 1.34 (90% CI, 1.19-1.48), which indicated thatdose-dependent increase in AUC_(inf) was slightly more thanproportional. These results were consistent with ANOVA sensitivityanalyses.

Thirteen participants (65%) reported a total of 31 AEs. The incidence ofAEs increased with increasing doses. Eight AEs (mainly headache [n=5/8])were experienced by 7 of 20 participants (35%) during the 4.5-g period,7 AEs (mainly gastrointestinal disorders [n=4/7]) were experienced by 4of 20 participants (20%) during the 7.5-g period; and 16 AEs (mainlygastrointestinal disorders [n=8/16]) were experienced by 6 of 12participants (50%) during the 9-g period. One of these, a nervous systemdisorder (sedation), was an SAE. This SAE was most likely a result oftreatment at 9 g without subsequent continuous titration through thelower doses of FT218; however, even without titration, AEs at the 9-gdose only occurred in 50% of participants and were mainly mild tomoderate in severity. All AEs were resolved before the end of the study.

Relative Bioavailability Study

The relative bioavailability study was a randomized, open-label,crossover study to evaluate the relative bioavailability of FT218compared with twice-nightly SO. Participants were randomized 1:1 to asingle dose of 6 g FT218 or 6 g twice-nightly SO (given as two 3-g doses4 h apart) with a washout period of ≥3 days between treatments. For thepilot, dose proportionality, and relative bioavailability studies, FT218or the first dose of twice-nightly SO was administered at approximately9:00 PM, 2 h after a standardized dinner (1251 kcal, 19.6 g of protein,25.5 g of fat, and 54.9 g of carbohydrate).

The relative bioavailability study included 28 individuals (10 men and18 women), with a mean (SD) age of 27 (9) years. Overall, 26 of 28participants completed both study phases per protocol, and the remaining2 participants withdrew prematurely owing to AEs.

In the relative bioavailability study, for FT218 treatment, bloodsamples were collected from all participants before dosing; at 10, 20,and 30 min after dosing; and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5,6, 7, 8, 10, 12, and 14 h after dosing. The same time points were usedin reference to the first dose of twice-nightly SO, omitting the3.5-hour collection; there were 2 additional collections at 10 and 20min after the second dose of twice-nightly SO (at 4 h, 10 min, and at 4h 20 min).

Once-nightly FT218 6 g had equivalent exposure with a lower overallC_(max) than twice-nightly SO at a total dose of 6 g (Table 20c and FIG.136 ). Mean (SE) AUC_(inf) of FT218 6 g (273 [27] h*μg/mL) metbioequivalence criteria compared with AUC_(inf) of twice-nightly SO 6 g(259 [22] h*μg/mL). Mean (SE) C_(max) of FT218 6 g (64.6 [5] μg/mL) waslower (below bioequivalence criteria) than overall Cmax of twice-nightlySO 6 g (70.9 [4] μg/mL). Mean (SE) AUC₀₋₈ of FT218 6 g (267 [27]h*μg/mL) also met bioequivalence criteria compared with AUC₀₋₈ oftwice-nightly SO 6 g (248 [18] h*μg/mL). Mean (SE) C_(8h) for FT218 6 g(6.6 [1]μg/mL) was lower (below equivalence criteria) than C_(8h) oftwice-nightly SO 6 g (10.7 [3]μg/mL). Interpatient variability betweenthe 2 treatments was similar for all pharmacokinetic parameters.

TABLE 20c Pharmacokinetic properties in the relative bioavailabilitystudy Twice-Nightly FT218 6 SO 6 g (First Dose) Parameter g (n = 26) (n= 27) T_(max), median (range), h 1.50 (0.3-3.5) 0.05 (0.3-2.0) C_(max),mean (SD), 64.6 (5) [40] 70.9 (4) [28] μg/mL [CV] AUC_(inf), mean (SD),273 (27) [51] 259 (22) [44] h*μg/mL [CV] AUC₀₋₈, mean (SD), 267 (27)[51] 248 (18) [39] h*μg/mL [CV] C_(8h), mean (SD), 6.6 (1) [108] 10.7(3) [145] μg/mL [CV]

The incidence and types of AEs were similar between the FT218 andtwice-nightly SO groups, and most were known SO-related AEs. The mostcommon AE during both treatments was somnolence, and all AEs were mildor moderate in severity. There were no SAEs during the study. Twoparticipants withdrew from the study after experiencing AEs, including 1event of nausea after FT218 treatment and 1 event of flulike symptomsafter twice-nightly SO treatment.

Food-Effect Study

The food-effect study was an open-label, 2-period, crossover,single-dose study to assess the effect of food on the pharmacokineticproperties of single-dose FT218 6 g. Participants were randomized 1:1 tosingle-dose FT218 6 g after a 10-hour overnight fast (fasted state) or30 min after a standardized, high-fat breakfast (fed state; 50% totalcontent of meal consisting of fat and 800e1000 kcal, of which 150 kcalwas derived from protein, 250 kcal derived from carbohydrate, and500-600 kcal derived from fat) with a minimum 3-day washout betweenstudy periods. For all studies, FT218 was administered orally as apowder reconstituted as a suspension in 50-70 mL of water. Twice-nightlySO was administered orally as a 500-mg/mL solution diluted in 60 mL ofwater in divided doses given 4 h apart. All treatments were administeredunder investigator supervision and were followed by a hospitalizationperiod of 16-36 h.

The food-effect study included 16 individuals (10 men and 6 women), witha mean (SD) age of 32 (13) years. A total of 15 of 16 participantscompleted the study per protocol. One individual discontinuedparticipation in the study because of vomiting after receiving FT218 inthe fasted state. Two individuals were also excluded from thepharmacokinetic analysis set because of vomiting.

In the food-effect study, during the fed and fasted study periods, bloodsamples were collected before dosing; at 10, 20, and 30 min afterdosing; and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12,and 14 h after dosing.

FT218 had lower C_(max) in the fed versus the fasted state, and exposuremet bioequivalence criteria (Table 20d and FIG. 137 ). Mean t_(max) was1 h longer in the fed versus the fasted state (1.5 vs 0.5 h). Mean (SE)C_(max) in the fed state (64.0 [5] μg/mL) was lower than in the fastedstate (90.5 [4] μg/mL) and was below the bioequivalence 80%-125%no-effect boundaries (mean fed:fasted ratio, 66.7%; 90% CI,58.2%-76.5%). Mean (SE) AUC_(inf) the fasted state (267 [24] h*μg/mL)was slightly higher than in the fed state (242 [24] h*μg/mL), but the90% CIs were within the 80%-125% no-effect boundaries for bioequivalence(mean fed:fasted ratio, 86.1%; 90% CI, 80.0%-92.7%).

TABLE 20d Pharmacokinetic properties in the food effect study FT218 6 gParameter Fed (n = 14) Fasted (n = 13) T_(max), median (range), h 1.50(0.5-2.5) 0.53 (0.33-1) C_(max), mean (SD), μg/mL [CV] 64.0 (5) [27.3]90.5 (4) [17.5] AUC_(inf), mean (SD), h*μg/mL [CV] 242 (24) [36.5] 267(24) [32] AUC₀₋₈, mean (SD), h*μg/mL [CV] 239 (23) [35.5] 266 (23)[31.2] C_(8h), mean (SD), μg/mL [CV] 2.09 (1) [150.5] 1.43 (1) [142.7]

The frequency of AEs was higher in the fasted versus the fed state (58AEs in all 16 participants [100%, with 54 potentially related to studytreatment] in the fasted state and 32 AEs in 13 participants [86.7%, 31potentially related to study treatment] in the fed state). This findingwas primarily driven by an increase in gastrointestinal disorders (37.5%in the fasted state vs 13.3% in the fed state; most commonly nausea andvomiting) and nervous system disorders (all participants in the fastedstate vs 80.0% in the fed state; most commonly somnolence anddizziness). All events were mild or moderate in severity, and no SAEswere reported.

Example 21: Labeling for FT218 Embodiment

Warning: Central Nervous System (CNS) Depression and Abuse and Misuse.

Central Nervous System Depression

Sodium oxybate is a CNS depressant. In clinical trials at recommendeddoses, obtundation and clinically significant respiratory depressionoccurred in adult patients treated with twice-nightly sodium oxybate(i.e., Xyrem). Many patients who received sodium oxybate during clinicaltrials in narcolepsy were receiving central nervous system stimulants.

Abuse and Misuse

Sodium oxybate is the sodium salt of gamma-hydroxybutyrate (GHB). Abuseor misuse of illicit GHB, either alone or in combination with other CNSdepressants, may be associated with CNS adverse reactions, includingseizure, respiratory depression, decreases in the level ofconsciousness, coma, and death.

Because of the risks of CNS depression and abuse and misuse, FT218 maybe available only through a restricted program under a Risk Evaluationand Mitigation Strategy (REMS) called the FT218 REMS Program usingcertified pharmacies. Prescribers and patients must enroll in theprogram.

Indications and Usage

FT218 is indicated for the treatment of cataplexy or excessive daytimesleepiness (EDS) in adults with narcolepsy.

Dosage and Administration

Dosing Information

The recommended starting dosage is 4.5 grams (g) per night administeredorally. Increase the dosage by 1.5 g per night at weekly intervals tothe effective dosage range of 6 g to 9 g per night orally. The dosagemay be gradually titrated based on efficacy and tolerability. Doseshigher than 9 g per night may not have been studied and may notordinarily be administered.

Important Administration Instructions

FT218 is taken as a single dose at bedtime. Prepare the dose of FT218prior to bedtime. Prior to ingestion, each dose of FT218 should besuspended in approximately ⅓ cup (approximately 80 mL) of water in themixing cup provided.

FT218 may be given without regard for meals.

Patients should take FT218 while in bed and lie down immediately afterdosing as FT218 may cause them to fall asleep abruptly without firstfeeling drowsy. Patients may often fall asleep within 5 minutes oftaking FT218, and will usually fall asleep within 15 minutes, though thetime it takes any individual patient to fall asleep may vary from nightto night. Rarely, patients may take up to 2 hours to fall asleep.Patients may remain in bed following ingestion of FT218.

Switching Patients from Twice-Nightly Sodium Oxybate

Patients who are currently being treated with twice-nightly sodiumoxybate may be switched to FT218 at the nearest equivalent dose (g pernight), e.g., 7.5 g sodium oxybate divided into two 3.75 g doses pernight to 7.5 g FT218 once per night.

Dosage Forms and Strengths

FT218 is a white to off-white powder for oral suspension provided innightly dose packets of 4.5 g, 6 g, 7.5 g, or 9 g.

Contraindications

FT218 is contraindicated for use in:

-   -   combination with sedative hypnotic agents.    -   combination with alcohol.    -   patients with succinic semialdehyde dehydrogenase deficiency.    -   patients with hepatic impairment.

Warnings and Precautions

Central Nervous System Depression

The active ingredient in FT218, sodium oxybate, is a central nervoussystem (CNS) depressant. In adult clinical trials at recommended doses,obtundation and clinically significant respiratory depression occurredin patients treated with twice-nightly sodium oxybate (i.e., Xyrem).FT218 is contraindicated in combination with alcohol and sedativehypnotics. The concurrent use of FT218 with other CNS depressants,including but not limited to opioid analgesics, benzodiazepines,sedating antidepressants or antipsychotics, sedating anti-epilepticdrugs, general anesthetics, muscle relaxants, and/or illicit CNSdepressants, may increase the risk of respiratory depression,hypotension, profound sedation, syncope, and death. If use of these CNSdepressants in combination with FT218 is required, dose reduction ordiscontinuation of one or more CNS depressants (including FT218) may beconsidered. In addition, if short-term use of an opioid (e.g., post- orperioperative) is required, interruption of treatment with FT218 may beconsidered. Consumption of alcohol while taking FT218 may result in amore rapid release of the dose of sodium oxybate.

Healthcare providers should caution patients about operating hazardousmachinery, including automobiles or airplanes, until they are reasonablycertain that FT218 does not affect them adversely (e.g., impairjudgment, thinking, or motor skills). Patients should not engage inhazardous occupations or activities requiring complete mental alertnessor motor coordination, such as operating machinery or a motor vehicle orflying an airplane, for at least 6 hours after taking FT218. Patientsshould be queried about CNS depression-related events upon initiation ofFT218 therapy and periodically thereafter. FT218 is available onlythrough a restricted program under a REMS.

Abuse and Misuse

FT218 is a Schedule III controlled substance. The active ingredient ofFT218, sodium oxybate or gamma-hydroxybutyrate (GHB), is a Schedule Icontrolled substance. Abuse of illicit GHB, either alone or incombination with other CNS depressants, is associated with CNS adversereactions, including seizure, respiratory depression, decreases in thelevel of consciousness, coma, and death. The rapid onset of sedation,coupled with the amnestic features of FT218, particularly when combinedwith alcohol, has proven to be dangerous for the voluntary andinvoluntary user (e.g., assault victim). Because illicit use and abuseof GHB have been reported, physicians should carefully evaluate patientsfor a history of drug abuse and follow such patients closely, observingthem for signs of misuse or abuse of GHB (e.g., increase in size orfrequency of dosing, drug-seeking behavior, feigned cataplexy).

FT218 REMS Program

Because of the risks of central nervous system depression andabuse/misuse, FT218 is available only through the FT218 REMS Program.Required components of the FT218 REMS Program are:

-   -   FT218 is only dispensed through certified specialty pharmacies.    -   Healthcare providers who prescribe FT218 must complete the        enrollment forms and comply with the requirements.    -   Pharmacists must complete the enrollment forms and comply with        the requirements.    -   To receive FT218, patients must understand the risks and        benefits of FT218.

Respiratory Depression and Sleep-Disordered Breathing

FT218 may impair respiratory drive, especially in patients withcompromised respiratory function. In overdoses, life-threateningrespiratory depression has been reported. In an adult study assessingthe respiratory-depressant effects of twice-nightly sodium oxybate atdoses up to 9 g per night in 21 patients with narcolepsy, nodose-related changes in oxygen saturation were demonstrated in the groupas a whole. One of the four patients with preexisting,moderate-to-severe sleep apnea had significant worsening of theapnea/hypopnea index during treatment.

In an adult study assessing the effects of twice-nightly sodium oxybate9 g per night in 50 patients with obstructive sleep apnea, twice-nightlysodium oxybate did not increase the severity of sleep-disorderedbreathing and did not adversely affect the average duration and severityof oxygen desaturation overall. However, there was a significantincrease in the number of central apneas in patients takingtwice-nightly sodium oxybate, and clinically significant oxygendesaturation (55%) was measured in three patients (6%) afteradministration, with one patient with-drawing from the study and twocontinuing after single brief instances of desaturation. Prescribersshould be aware that increased central apneas and clinically relevantdesaturation events have been observed with twice-nightly administrationin adult patients.

In adult clinical trials in 128 patients with narcolepsy administeredtwice-nightly sodium oxybate, two subjects had profound CNS depression,which resolved after supportive respiratory intervention. Two otherpatients discontinued twice-nightly sodium oxybate because of severedifficulty breathing and an increase in obstructive sleep apnea. Therewere no cases of profound CNS depression or severe difficulty breathingin adult clinical trials in 212 patients with narcolepsy administeredFT218; there was one patient with worsening sleep apnea in both theFT218 and placebo-treated groups. In two controlled trials assessing PSGmeasures in adult patients with narcolepsy administered twice-nightlysodium oxybate, 40 of 477 patients were included with a baselineapnea/hypopnea index of 16 to 67 events per hour, indicative of mild tosevere sleep-disordered breathing. None of the 40 patients had aclinically significant worsening of respiratory function as measured byapnea/hypopnea index and pulse oximetry at doses of 4.5 g to 9 g pernight. In adult clinical trials of FT218 in patients with narcolepsy, nosub-jects with apnea/hypopnea indexes greater than 15 were allowed toenroll. Prescribers should be aware that sleep-related breathingdisorders tend to be more prevalent in obese patients, in men, inpostmenopausal women not on hormone replacement therapy and amongpatients with narcolepsy.

Depression and Suicidality

In an adult clinical trial in patients with narcolepsy (n=212)administered FT218, there were no suicide attempts and one patientdeveloped suicidal ideation at the 9 g dose. In adult clinical trials inpatients with narcolepsy (n=781) administered twice-nightly sodiumoxybate, there were two suicides and two attempted suicides in patientstreated with twice-nightly sodium oxybate, including three patients witha previous history of depressive psychiatric disorder. Of the twosuicides, one patient used twice-nightly sodium oxybate in conjunctionwith other drugs. Twice-nightly sodium oxybate was not involved in thesecond suicide. Adverse reactions of depression were reported by 7% of781 patients treated with twice-nightly sodium oxybate, with fourpatients (<1%) discontinuing because of depression. In most cases, nochange in twice-nightly sodium oxybate treatment was required.

In a controlled trial in adults with narcolepsy administered FT218(n=212) where patients were titrated from 4.5 g to 9 g per night, theincidences of depression were 0 at 4.5 g, 1 (1%) at 6 g, 1 (1.1%) at 7.5g and 1 (1.3%) at 9 g. In a controlled adult trial, with patientsrandomized to fixed doses of 3 g, 6 g, or 9 g per night twice-nightlysodium oxybate or placebo, there was a single event of depression at the3 g per night dose. In another adult controlled trial, with patientstitrated from an initial 4.5 g per night starting dose of twice-nightlysodium oxybate, the incidences of depression were 1 (1.7%), 1 (1.5%), 2(3.2%), and 2 (3.6%) for the placebo, 4.5 g, 6 g, and 9 g per nightdoses, respectively. The emergence of depression in patients treatedwith FT218 requires careful and immediate evaluation. Patients with aprevious history of a depressive illness and/or suicide attempt shouldbe monitored carefully for the emergence of depressive symptoms whiletaking FT218.

Other Behavioral or Psychiatric Adverse Reactions

During adult clinical trials in patients with narcolepsy administeredFT218, 2% of 107 patients treated with FT218 experienced a confusionalstate. During adult clinical trials in patients with narcolepsyadministered twice-nightly sodium oxybate, 3% of 781 patients treatedwith twice-nightly sodium oxybate experienced confusion, with incidencegenerally increasing with dose. No patients treated with FT218discontinued treatment because of confusion. Less than 1% of patientsdiscontinued the twice-nightly sodium oxybate because of confusion.Confusion was reported at all recommended doses from 6 g to 9 g pernight. In a controlled trial in adults where patients were randomized totwice-nightly sodium oxybate in fixed total daily doses of 3 g, 6 g, or9 g per night or placebo, a dose-response relationship for confusion wasdemonstrated, with 17% of patients at 9 g per night experiencingconfusion. In all cases in that controlled trial, the confusion resolvedsoon after termination of treatment. In one trial, where twice-nightlysodium oxybate was titrated from an initial 4.5 g per night dose, therewas a single event of confusion in one patient at the 9 g per nightdose. In the majority of cases in all adult clinical trials in patientswith narcolepsy administered twice-nightly sodium oxybate, confusionresolved either soon after termination of dosing or with continuedtreatment.

Anxiety occurred in 7.5% of 107 patients treated with FT218 in the adulttrial in patients with narcolepsy. In the study, 16.5% of narcolepsypatients had anxiety at study entry. Anxiety occurred in 5.8% of the 874patients receiving twice-nightly sodium oxybate in adult clinical trialsin another population. Other psychiatric reactions reported in adultclinical trials in patients with narcolepsy administered FT218 includedirritability, emotional disorder, panic attack, agitation, delirium, andobsessive thoughts. Other neuropsychiatric reactions reported in adultclinical trials in patients with narcolepsy administered twice-nightlysodium oxybate and the post-marketing setting for twice-nightly sodiumoxybate included hallucinations, paranoia, psychosis, aggression, andagitation. The emergence or increase in the occurrence of behavioral orpsychiatric events in adult patients taking FT218 should be carefullymonitored.

Parasomnias

Sleepwalking, defined as confused behavior occurring at night and attimes associated with wandering was reported in 3% of 107 patients withnarcolepsy treated with FT218. No patients treated with FT218discontinued due to sleepwalking. Sleepwalking was reported in 6% of 781patients with narcolepsy treated with twice-nightly sodium oxybate inadult controlled and long-term open-label studies, with <1% of patientsdiscontinuing due to sleepwalking. Rates of sleepwalking were similarfor patients taking placebo and patients taking twice-nightly sodiumoxybate in controlled trials. It is unclear if some or all of thereported sleepwalking episodes correspond to true somnambulism, which isa parasomnia occurring during non-REM sleep, or to any other specificmedical disorder. Five instances of sleepwalking with potential injuryor significant injury were reported during a clinical trial oftwice-nightly sodium oxybate in patients with narcolepsy. Parasomnias,including sleepwalking, also have been reported in the postmarketingexperience with twice-nightly sodium oxybate. Therefore, episodes ofsleepwalking should be fully evaluated and appropriate interventionsconsidered.

Use in Patients Sensitive to High Sodium Intake

FT218 has a high salt content. In patients sensitive to salt intake(e.g., those with heart failure, hypertension, or renal impairment),consider the amount of daily sodium intake in each dose of FT218. Table21 provides the approximate sodium content per FT218 dose.

TABLE 21 Approximate Sodium Content per Total Nightly Dose of FT218 (g =grams) FT218 Dose Sodium Content/Total Nightly Exposure 4.5 g per night 820 mg   6 g per night 1094 mg 7.5 g per night 1367 mg   9 g per night1641 mg

Adverse Reactions

The following clinically significant adverse reactions appear in othersections of the labeling:

-   -   CNS depression    -   Abuse and Misuse    -   Respiratory Depression and Sleep-Disordered Breathing    -   Depression and Suicidality    -   Other Behavioral or Psychiatric Adverse Reactions    -   Parasomnias    -   Use in Patients Sensitive to High Sodium Intake

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions,adverse reaction rates observed in the clinical trials of a drug cannotbe directly compared to rates in the clinical trials of another drug andmay not reflect the rates observed in clinical practice.

Adult Patients

FT218 was studied in one placebo-controlled trial (Study 1) in 212patients with narcolepsy (107 subjects treated with FT218 and 105 withplacebo).

Most Common Adverse Reactions:

The most common adverse reactions (incidence>50 and greater thanplacebo) reported for all doses of FT218 combined were nausea,dizziness, enuresis, headache, decreased appetite, vomiting, andanxiety.

Adverse Reactions Occurring at an Incidence of 2% or Greater:

Table 22 lists adverse reactions occurring in 2% or more ofFT218-treated patients on any individual dose and at a rate greater thanplacebo-treated patients in Study 1.

Adverse Reactions Leading to TreatmentDiscontinuation:

Of the 212 patients with narcolepsy treated with FT218, 15.9%discontinued because of adverse reactions compared to 1.900 of patientsreceiving placebo. For FT218, 5.60% of patients discontinued due toadverse reactions on 4.5 g, 4.1% on 6 g, 4.5% on 7.5 g and 3.9% on 9 gdose.

TABLE 22 Adverse reactions occurring in 2% or more of FT218-treatedpatients on any individual dose and for which the rate for FT218-treatedpatients exceeds the rate for placebo-treated patients in Study 1. Week1 Weeks 2-3 Weeks 4-8 Weeks 9-13 System Organ FT218 FT218 FT218 FT218Class/Adverse Placebo 4.5 g Placebo 6 g Placebo 7.5 g Placebo 9 gReaction (N = 107) (N = 105) (N = 97) (N = 102) (N = 88) (N = 88) (N =77) (N = 80) Gastrointestinal Disorders Vomiting 1 3 1 3 0 6 0 5 Nausea1 6 2 8 0 7 1 1 Investigations Weight 0 1 0 0 0 0 0 4 DecreasedMetabolism and Nutritional Disorders Decreased 0 4 0 4 0 3 0 3 AppetiteNervous System Disorders Dizziness 0 6 0 4 0 6 0 5 Somnolence 1 0 0 1 02 1 4 Headache 4 8 1 5 1 6 0 1 Psychiatric Disorders Enuresis 0 2 0 4 09 0 9 Anxiety 0 3 0 1 1 3 0 1 Somnambulism 0 1 0 2 0 0 0 0

Adverse Reactions Leading to Treatment Discontinuation:

Of the 212 patients with narcolepsy treated with FT218, 15.9%discontinued because of adverse reactions compared to 1.9% of patientsreceiving placebo. For FT218, 5.6% of patients discontinued due toadverse reactions on 4.5 g, 4.1% on 6 g, 4.5% on 7.5 g and 3.9% on 9 gdose.

Dose-Response Information

In clinical trials in adult patients with narcolepsy, a dose-responserelationship was observed for enuresis.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of twice-nightly sodium oxybate. Because these reactionsare reported voluntarily from a population of uncertain size, it is notalways possible to reliably estimate their frequency or establish acausal relation-ship to drug exposure: arthralgia, decreased appetite,fall, fluid retention, hangover, headache, hypersensitivity,hyper-tension, memory impairment, nocturia, panic attack, visionblurred, and weight decreased. The sudden onset of sleep in patientstaking twice-nightly sodium oxybate, including in a standing position orwhile rising from bed, has led to falls complicated by injuries, in somecases requiring hospitalization.

Drug Interactions

Alcohol, Sedative Hypnotics, and CNS Depressants

FT218 is contraindicated for use in combination with alcohol or sedativehypnotics. Use of other CNS depressants may potentiate theCNS-depressant effects of FT218. Consumption of alcohol while takingFT218 may result in a more rapid release of the dose of sodium oxybate.

Use in Specific Populations

Pregnancy Risk Summary

There are no adequate data on the developmental risk associated with theuse of sodium oxybate in pregnant women. Oral administration of sodiumoxybate to pregnant rats (150, 350, or 1,000 mg/kg/day) or rabbits (300,600, or 1,200 mg/kg/day) throughout organogenesis produced no clearevidence of developmental toxicity; however, oral administration to ratsthroughout pregnancy and lactation resulted in increased stillbirths anddecreased offspring postnatal viability and growth, at a clinicallyrelevant dose. In the U.S. general population, the estimated backgroundrisk of major birth defects and miscarriage in clinically recognizedpregnancies is 24% and 15-20%, respectively. The background risk ofmajor birth defects and miscarriage for the indicated population isunknown.

Clinical Considerations for Labor or Delivery

FT218 has not been studied in labor or delivery. In obstetric anesthesiausing an injectable formulation of sodium oxybate, newborns had stablecardiovascular and respiratory measures but were very sleepy, causing aslight decrease in Apgar scores. There was a fall in the rate of uterinecontractions 20 minutes after injection. Placental transfer is rapid andgamma-hydroxybutyrate (GHB) has been detected in newborns at deliveryafter intravenous administration of GHB to mothers. Subsequent effectsof sodium oxybate on later growth, development, and maturation in humansare unknown.

Animal Data

Oral administration of sodium oxybate to pregnant rats (150, 350, or1,000 mg/kg/day) or rabbits (300, 600, or 1,200 mg/kg/day) throughoutorganogenesis produced no clear evidence of developmental toxicity. Thehighest doses tested in rats and rabbits were approximately 1 and 3times, respectively, the maximum recommended human dose (MRHD) of 9 gper night on a body surface area (mg/m²) basis. Oral administration ofsodium oxybate (150, 350, or 1,000 mg/kg/day) to rats throughoutpregnancy and lactation resulted in increased stillbirths and decreasedoffspring postnatal viability and body weight gain at the highest dosetested. The no-effect dose for pre- and post-natal developmentaltoxicity in rats is less than the MRHD on a mg/m² basis.

Lactation Risk Summary

GHB is excreted in human milk after oral administration of sodiumoxybate. There is insufficient information on the risk to a breastfedinfant, and there is insufficient information on milk production innursing mothers. The developmental and health benefits of breastfeedingshould be considered along with the mother's clinical need for FT218 andany potential adverse effects on the breastfed infant from FT218 or fromthe underlying maternal condition.

Pediatric Use

The safety and effectiveness of FT218 in the treatment of cataplexy orexcessive daytime sleepiness in pediatric patients have not beenestablished.

Geriatric Use

Clinical studies of FT218 in patients with narcolepsy did not includesufficient numbers of subjects age 65 years and older to determinewhether they respond differently from younger subjects. In controlledtrials of twice-nightly sodium oxybate in another population, 39 (5%) of874 patients were 65 years or older. Discontinuations of treatment dueto adverse reactions were increased in the elderly compared to youngeradults (21% v. 19%). Frequency of headaches was markedly increased inthe elderly (39% v. 19%). The most common adverse reactions were similarin both age categories. In general, dose selection for an elderlypatient should be cautious, usually starting at the low end of thedosing range, reflecting the greater frequency of decreased hepatic,renal, or cardiac function, and of concomitant disease or other drugtherapy.

Hepatic Impairment

Because of an increase in exposure to FT218, FT218 should not beadministered to patients with liver impairment.

Drug Abuse and Dependence

Controlled Substance

FT218 is a Schedule III controlled substance under the FederalControlled Substances Act. Non-medical use of FT218 could lead topenalties assessed under the higher Schedule I controls.

Abuse

FT218 (sodium oxybate), the sodium salt of GHB, produces dose-dependentcentral nervous system effects, including hypnotic and positivesubjective reinforcing effects. The onset of effect is rapid, enhancingits potential for abuse or misuse.

Drug abuse is the intentional non-therapeutic use of a drug product orsubstance, even once, for its desirable psychological or physiologicaleffects. Misuse is the intentional use, for therapeutic purposes of adrug by an individual in a way other than prescribed by a health careprovider or for whom it was not prescribed. Drug misuse and abuse mayoccur with or without progression to addiction. Drug addiction is acluster of behavioral, cognitive, and physiological phenomena that mayinclude a strong desire to take the drug, difficulties in controllingdrug use (e.g., continuing drug use despite harmful consequences, givinga higher priority to drug use than other activities and obligations),and possible tolerance or physical dependence.

The rapid onset of sedation, coupled with the amnestic features of GHB,particularly when combined with alcohol, has proven to be dangerous forthe voluntary and involuntary user (e.g., assault victim).

Illicit GHB is abused in social settings. Some of the doses estimated tobe abused are in a similar dosage range to that used for treatment ofpatients with cataplexy. GHB has some commonalities with ethanol over alimited dose range, and some cross tolerance with ethanol has beenreported as well. Cases of severe dependence and craving for GHB havebeen reported when the drug is taken around the clock. Patterns of abuseindicative of dependence include: 1) the use of increasingly largedoses, 2) increased frequency of use, and 3) continued use despiteadverse consequences.

Because illicit use and abuse of GHB have been reported, physiciansshould carefully evaluate patients for a history of drug abuse andfollow such patients closely, observing them for signs of misuse orabuse of GHB (e.g., increase in size or frequency of dosing,drug-seeking behavior, feigned cataplexy). Dispose of FT218 according tostate and federal regulations. It is safe to dispose of FT218 down thesanitary sewer.

Dependence

Physical dependence is a state that develops as a result ofphysiological adaptation in response to repeated drug use, manifested bywithdrawal signs and symptoms after abrupt discontinuation or asignificant dose reduction of a drug. There have been case reports ofwithdrawal, ranging from mild to severe, following discontinuation ofillicit use of GHB at frequent repeated doses (18 g to 250 g per day) inexcess of the recommended dosage range. Signs and symptoms of GHBwithdrawal following abrupt discontinuation included insomnia,restlessness, anxiety, psychosis, lethargy, nausea, tremor, sweating,muscle cramps, tachycardia, headache, dizziness, rebound fatigue andsleepiness, confusion, and, particularly in the case of severewithdrawal, visual hallucinations, agitation, and delirium. Thesesymptoms generally abated in 3 to 14 days. In cases of severewithdrawal, hospitalization may be required. The discontinuation effectsof FT218 have not been systematically evaluated in controlled clinicaltrials. In the clinical trial experience with FT218, there were noreported reactions occurring following abrupt discontinuation of FT218.In the clinical trial experience with twice-nightly sodium oxybate innarcolepsy/cataplexy patients at recommended doses, two patientsreported anxiety and one reported insomnia following abruptdiscontinuation at the termination of the clinical trial; in the twopatients with anxiety, the frequency of cataplexy had increased markedlyat the same time.

Tolerance

Tolerance is a physiological state characterized by a reduced responseto a drug after repeated administration (i.e., a higher dose of a drugis required to product the same effect that was once obtained at a lowerdose). Tolerance to FT218 has not been systematically studied incontrolled clinical trials. There have been some case reports ofsymptoms of tolerance developing after illicit use at dosages far inexcess of the recommended FT218 dosage regimen. Clinical studies oftwice-nightly sodium oxybate in the treatment of alcohol withdrawalsuggest a potential cross-tolerance with alcohol. The safety andeffectiveness of FT218 in the treatment of alcohol withdrawal have notbeen established.

Overdosage

Human Experience

Information regarding overdose with FT218 is derived largely fromreports in the medical literature that describe symptoms and signs inindividuals who have ingested GHB illicitly. In these circumstances theco-ingestion of other drugs and alcohol was common, and may haveinfluenced the presentation and severity of clinical manifestations ofoverdose. There were no cases of overdose in adult clinical trials ofFT218. In adult clinical trials of twice-nightly sodium oxybate, twocases of overdose with sodium oxybate were reported. In the first case,an estimated dose of 150 g, more than 15 times the maximum recommendeddose, caused a patient to be unresponsive with brief periods of apneaand to be incontinent of urine and feces. This individual recoveredwithout sequelae. In the second case, death was reported following amultiple drug overdose consisting of sodium oxybate and numerous otherdrugs.

Signs and Symptoms

Information about signs and symptoms associated with overdosage withFT218 derives from reports of illicit use of GHB. Patient presentationfollowing overdose is influenced by the dose ingested, the time sinceingestion, the co-ingestion of other drugs and alcohol, and the fed orfasted state. Patients have exhibited varying degrees of depressedconsciousness that may fluctuate rapidly between a confusional, agitatedcombative state with ataxia and coma. Emesis (even when obtunded),diaphoresis, headache, and impaired psychomotor skills have beenobserved. No typical pupillary changes have been described to assist indiagnosis; pupillary reactivity to light is maintained. Blurred visionhas been reported. An increasing depth of coma has been observed athigher doses. Myoclonus and tonic-clonic seizures have been reported.Respiration may be unaffected or compromised in rate and depth.Cheyne-Stokes respiration and apnea have been observed. Bradycardia andhypothermia may accompany unconsciousness, as well as muscularhypotonia, but tendon reflexes remain intact.

Recommended Treatment of Overdose

General symptomatic and supportive care should be institutedimmediately, and gastric decontamination may be considered ifcoingestants are suspected. Because emesis may occur in the presence ofobtundation, appropriate posture (left lateral recumbent position) andprotection of the airway by intubation may be warranted. Although thegag reflex may be absent in deeply comatose patients, even unconsciouspatients may become combative to intubation, and rapid-sequenceinduction (without the use of sedative) should be considered. Vitalsigns and consciousness should be closely monitored. The bradycardiareported with GHB overdose has been responsive to atropine intravenousadministration. No reversal of the central depressant effects of FT218can be expected from naloxone or flumazenil administration. The use ofhemodialysis and other forms of extracorporeal drug removal have notbeen studied in GHB overdose. However, due to the rapid metabolism ofsodium oxybate, these measures are not warranted.

Poison Control Center

As with the management of all cases of drug overdosage, the possibilityof multiple drug ingestion should be considered. The healthcare provideris encouraged to collect urine and blood samples for routine toxicologicscreening, and to consult with a regional poison control center(1-800-222-1222) for current treatment recommendations.

Description

Sodium oxybate, a CNS depressant, is the active ingredient in FT218. Thechemical name for sodium oxybate is sodium 4-hydroxybutyrate. Themolecular formula is C₄H₇NaO₃, and the molecular weight is 126.09g/mole. The chemical structure is:

Sodium oxybate is white to off-white solid powder. Each nightly dosepacket contains a blend of immediate-release and controlled-releasegranules of FT218 providing doses of 4.5 g, 6 g, 7.5 g, or 9 g of sodiumoxybate. The inactive ingredients are microcrystalline cellulosespheres, povidone K30, hydrogenated vegetable oil, methacrylic acidcopolymer, malic acid, xanthan gum, hydroxyethyl cellulose, carrageenan,and magnesium stearate.

Clinical Pharmacology

Mechanism of Action

FT218 is a CNS depressant. The mechanism of action of FT218 in thetreatment of narcolepsy is unknown. Sodium oxybate is the sodium salt ofgamma-hydroxybutyrate (GHB), an endogenous compound and metabolite ofthe neurotransmitter GABA. It is hypothesized that the therapeuticeffects of FT218 on cataplexy and excessive daytime sleepiness aremediated through GABA_(B) actions at noradrenergic and dopaminergicneurons, as well as at thalamocortical neurons.

Pharmacokinetics

Following oral administration of twice-nightly sodium oxybate, GHB isabsorbed rapidly across the clinical dose range, with an absolutebioavailability of about 88%. Following oral administration of FT218,the peak plasma concentrations (C_(max)) following administration of one6 g dose was 65.8 mcg/mL and the time to peak plasma concentration(T_(max)) was 1.51 hours. Following oral administration of FT218, theplasma levels of GHB increased dose-proportionally, with blood levelsincreasing 2-fold as total daily dose is doubled from 4.5 g to 9 g.

Effect of Food

The AUC data from a food-effect study involving administration of FT218to healthy volunteers under fasting conditions and with a high-fat mealindicated that exposure to the drug is not affected by food. Althoughadministration of FT218 immediately after a high-fat meal resulted indelayed absorption (average T_(max) increased from 0.53 hr to 1.5 hr)and a reduction in C_(max) of GHB by a mean of 33.3%, these changes arenot clinically relevant. Therefore, FT218 may be taken without regard tomeals.

Effect of Ethanol

An in vitro ethanol interaction demonstrated that >90% of anadministered dose of FT218 may be released within 1 hour, ifadministered at the same time as alcohol is ingested.

Distribution

GHB is a hydrophilic compound with an apparent volume of distributionaveraging 190 mL/kg to 384 mL/kg. At GHB concentrations ranging from 3mcg/mL to 300 mcg/mL, less than 1% is bound to plasma proteins.

Elimination and Metabolism

Animal studies indicate that metabolism is the major elimination pathwayfor GHB, producing carbon dioxide and water via the tricarboxylic acid(Krebs) cycle and secondarily by beta-oxidation. The primary pathwayinvolves a cytosolic NADP+-linked enzyme, GHB dehydrogenase, thatcatalyzes the conversion of GHB to succinic semialdehyde, which is thenbiotransformed to succinic acid by the enzyme succinic semialdehydedehydrogenase. Succinic acid enters the Krebs cycle where it ismetabolized to carbon dioxide and water. A second mitochondrialoxidoreductase enzyme, a transhydrogenase, also catalyzes the conversionto succinic semialdehyde in the presence of α-ketoglutarate. Analternate pathway of biotransformation involves β-oxidation via3,4-dihydroxybutyrate to carbon dioxide and water. No active metaboliteshave been identified.

Excretion

The clearance of GHB is almost entirely by biotransformation to carbondioxide, which is then eliminated by expiration. On average, less than5% of unchanged drug appears in human urine within 6 to 8 hours afterdosing. Fecal excretion is negligible. GHB has an elimination half-lifeof 0.5 to 1 hour.

Specific Populations

Geriatric Patients

There is limited experience with FT218 in the elderly. Results from apharmacokinetic study of twice-nightly sodium oxybate (n=20) in anotherstudied population indicate that the pharmacokinetic characteristics ofGHB are consistent among younger (age 48 to 64 years) and older (age 65to 75 years) adults.

Pediatric Patients

The pharmacokinetics of sodium oxybate in patients younger than 18 yearsof age have not been studied.

Male and Female Patients

In a study of 18 female and 18 male healthy adult volunteers, no genderdifferences were detected in the pharmacokinetics of GHB following asingle twice nightly sodium oxybate oral dose of 4.5 g.

Racial or Ethnic Groups

There are insufficient data to evaluate any pharmacokinetic differencesamong races

Patients with Renal Impairment

No pharmacokinetic study in patients with renal impairment has beenconducted.

Patients with Hepatic Impairment

The pharmacokinetics of GHB in 16 cirrhotic patients, half withoutascites (Child's Class A) and half with ascites (Child's Class C), werecompared to the kinetics in 8 subjects with normal hepatic functionafter a single sodium oxybate oral dose of 25 mg/kg. AUC values weredouble in the cirrhotic patients, with apparent oral clearance reducedfrom 9.1 mL/min/kg in healthy adults to and 4.1 mL/min/kg in Class A andClass C patients, respectively. Elimination half-life was significantlylonger in Class C and Class A patients than in control patients (meant_(1/2) of 59 and 32 minutes, respectively, versus 22 minutes in controlpatients). FT218 should not be administered to patients with liverimpairment.

Drug Interaction Studies

Studies in vitro with pooled human liver microsomes indicate that sodiumoxybate does not significantly inhibit the activities of the humanisoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A up to theconcentration of 3 mM (378 mcg/mL), a level considerably higher thanlevels achieved with recommended doses.

Drug interaction studies in healthy adults (age 18 to 50 years) wereconducted with FT218 and divalproex sodium:

Divalproex sodium: Co-administration of a single dose of FT218 (6 g)with a single dose of divalproex sodium ER (1250 mg) resulted incomparable systemic exposure to GHB as shown by plasma C_(max) and AUCvalues. Co-administration did not appear to affect the pharmacokineticsof divalproex sodium and no dose adjustment is recommended forconcomitant administration with FT218 based on this pharmacokineticobservation.

Drug interaction studies in healthy adults (age 18 to 50 years) wereconducted with twice-nightly sodium oxybate and diclofenac andibuprofen:

Diclofenac: Co-administration of sodium oxybate (6 g per day as twoequal doses of 3 grams dosed four hours apart) with diclofenac (50mg/dose twice per day) showed no significant differences in systemicexposure to GHB. Co-administration did not appear to affect thepharmacokinetics of diclofenac.

Ibuprofen: Co-administration of sodium oxybate (6 g per day as two equaldoses of 3 grams dosed four hours apart) with ibuprofen (800 mg/dosefour times per day also dosed four hours apart) resulted in comparablesystemic exposure to GHB as shown by plasma C_(max) and AUC values.Co-administration did not affect the pharmacokinetics of ibuprofen.

Drug interaction studies in healthy adults demonstrated nopharmacokinetic interactions be-tween twice-nightly sodium oxybate andprotriptyline hydrochloride, zolpidem tartrate, and modafinil. Also,there were no pharmacokinetic interactions with the alcoholdehydrogenase inhibitor fomepizole. However, pharmacodynamicinteractions with these drugs cannot be ruled out. Alteration of gastricpH with omeprazole produced no significant change in thepharmacokinetics of GHB. In addition, drug interaction studies inhealthy adults demonstrated no pharmacokinetic or clinically significantpharmacodynamic interactions between twice-nightly sodium oxybate andduloxetine HCl.

Nonclinical Toxicology

Carcinogenesis

Administration of sodium oxybate to rats at oral doses of up to 1,000mg/kg/day for 83 (males) or 104 (females) weeks resulted in no increasein tumors. Plasma exposure (AUC) at the highest dose tested was 2 timesthat in humans at the maximum recommended human dose (MRHD) of 9 g pernight.

The results of 2-year carcinogenicity studies in mouse and rat withgamma-butyrolactone, a compound that is metabolized to sodium oxybate invivo, showed no clear evidence of carcinogenic activity. The plasma AUCsof sodium oxybate achieved at the highest doses tested in these studieswere less than that in humans at the MRHD.

Mutagenesis

Sodium oxybate was negative in the in vitro bacterial gene mutationassay, an in vitro chromosomal aberration assay in mammalian cells, andin an in vivo rat micronucleus assay.

Impairment of Fertility

Oral administration of sodium oxybate (150, 350, or 1,000 mg/kg/day) tomale and female rats prior to and throughout mating and continuing infemales through early gestation resulted in no adverse effects onfertility. The highest dose tested is approximately equal to the MRHD ona mg/m² basis.

Clinical Studies

The efficacy of FT218 for the treatment of cataplexy or excessivedaytime sleepiness (EDS) in adults with narcolepsy has been establishedbased on a double-blind, randomized, placebo-controlled, two armmulti-center study to assess the efficacy and safety of a once nightlyadministration of FT218 in patients with narcolepsy (Study 1).

A total of 212 subjects were randomized to the active or placebo arm ina 1:1 ratio. The study is divided into four sequential study periods andincorporates dose titration to stabilized dose administration of FT218(4.5 g, 6 g, 7.5 g, and 9 g). There was a three-week screening period, a13-week treatment period including up-titration over a period of eightweeks and five weeks of stable dosing at 9 g/night, and a one-weekfollow-up period. Patients could be on concomitant stimulant use as longas it was stable for 3 weeks prior to study start.

The three co-primary endpoints were the Maintenance of Wakefulness Test(MWT), Clinical Global Impression-Improvement (CGI-I) and mean change inweekly cataplexy attacks. The Epworth Sleepiness Scale was a secondaryendpoint in the study. The Maintenance of Wakefulness Test measureslatency to sleep onset (in minutes) averaged over five sessions at2-hour intervals following nocturnal polysomnography. For each testsession, patients were instructed to remain awake for as long aspossible during 30-minute test sessions, and sleep latency wasdetermined as the number of minutes patients could remain awake. Theoverall score is the mean sleep latency for the 5 sessions. The ClinicalGlobal Impression-Improvement is evaluated on a 7-point scale, centeredat No Change and ranging from Very Much Worse to Very Much Improved.Patients were rated by evaluators who based their assessments on theseverity of narcolepsy at Baseline.

Demographic and mean Baseline characteristics were similar for the FT218and placebo groups. A total of 76% were NT1 patients and 24% were NT2patients. Mean age was 31.2 years and 68% was female. Approximately 63%patients were on concomitant stimulant use. The mean MWT at Baseline was5 minutes for the FT218 group and 4.7 minutes for the placebo group. Themean number of cataplexy attacks per week at Baseline was 18.9 in theFT218 group and 19.8 in the placebo group. For the three coprimaryendpoints, statistically significant improvement was seen on theMaintenance of Wakefulness Test, Clinical Global Impression-Improvementand mean weekly cataplexy attacks for the 6 g (Week 3), 7.5 g (Week 8)and 9 g (Week 13) dose of FT218 compared to the placebo group (see Table23, Table 24 and Table 25). Results (MWT and CGI-I) were consistentbetween NT1 and NT2 patients as well as patients on stimulants comparedto those not on stimulants.

TABLE 23 Change from Baseline in the Maintenance of Wakefulness Test (inminutes) Treatment Difference Group Change from from Placebo Dose (N)Baseline (SE) [95% CI] p-value   6 g (Week 3) FT218 (87)  8.08 (0.75)4.98 [2.90; 7.05] <0.001 Placebo (88)  3.10 (0.74) 7.5 g (Week 8) FT218(76)  9.55 (0.86) 6.21 [3.84; 8.58] <0.001 Placebo (78)  3.34 (0.84)   9g (Week 13) FT218 (68) 10.82 (0.96) 6.13 [3.52, 8.75] <0.001 Placebo(78)  4.690.92) Mean (SD) MWT at Baseline was 4.99 (3.15) minutes forthe FT218 group and 4.73 (2.58) minutes for the placebo group.

TABLE 24 Proportion of Patients with a Very Much or Much ImprovedClinical Global Impression-Improvement Percentage of RespondersTreatment (Much or Very Odds Ratio Dose Group (N) Much Improved) [95%CI] p-value   6 g (Week 3) FT218 (87) 40.1 10.29 <0.001 [3.93; 26.92]Placebo (87) 6.1 — — 7.5 g (Week 8) FT218 (75) 62.6 5.67 <0.001 [2.82;11.40] Placebo (81) 22.8 — —   9 g (Week 13) FT218 (69) 72.0 5.56 <0.001[2.76; 11.23] Placebo (79) 31.6 — —

TABLE 25 Change from Baseline in the Mean Cataplexy Attacks Per WeekDifference Treatment Change from from Placebo Dose Group (N) Baseline(SE) [95% CI] p-value   6 g (Week 3) FT218 (55)  −7.42 (0.79) −4.83<0.001 [−7.03; −2.62] Placebo (62)  −2.59 (0.79) — — 7.5 g (Week 8)FT218 (66)  −9.98 (0.88) −6.23 <0.001 [−8.74; −3.80] Placebo (69)  −3.71(0.88) — —   9 g (Week 13) FT218 (73) −11.51 (0.96) −6.65 <0.001 [−9.32;−3.98] Placebo (72)  −4.86 (0.945) — — Mean (SD) number of cataplexyattacks per week at Baseline was 18.93 (8.70) in the FT218 group and19.82 (8.87) in the placebo group.

How Supplied/Storage and Handling

How Supplied

FT218 is a blend of white to off-white granules for oral suspension inwater. Each prescription includes nightly dose packets of FT218 with amixing cup.

Dose packets contain a single dose of FT218 provided in 4.5 g, 6 g, 7.5g, and 9 g doses.

Storage

Keep out of reach of children. FT218 should be stored at 25° C. (77°F.); excursions permitted to 15° to 30° C. (59° to 86° F.) (see USPControlled Room Temperature). Suspensions should be consumed within 30minutes.

Handling and Disposal

FT218 is a Schedule III drug under the Controlled Substances Act. FT218should be handled according to state and federal regulations. It is safeto dispose of FT218 down the sanitary sewer.

Patient Counseling Information

Advise the patient and/or caregiver to read the FDA-approved patientlabeling (Medication Guide and Instructions for Use).

Central Nervous System Depression

Inform patients and/or caregivers that FT218 can cause central nervoussystem depression, including respiratory depression, hypotension,profound sedation, syncope, and death. Instruct patients to not engagein activities requiring mental alertness or motor coordination,including operating hazardous machinery, for at least 6 hours aftertaking FT218. Instruct patients and/or their caregivers to inform theirhealthcare providers of all the medications they take.

Abuse and Misuse

Inform patients and/or caregivers that the active ingredient of FT218 isgamma-hydroxybutyrate (GHB), which is associated with serious adversereactions with illicit use and abuse.

FT218 REMS Program

Inform patients that FT218 is available only through the FT218 REMSProgram. The contents of the FT218 Medication Guide and educationalmaterials are reviewed with every patient before initiating treatmentwith FT218.

Patients must read and understand the materials in the FT218 REMSProgram prior to initiating treatment. Inform the patient that theyshould be seen by the prescriber frequently to review dose titration,symptom response, and adverse reactions; a follow-up of every threemonths is recommended.

Discuss safe and proper use of FT218 and dosing information withpatients prior to the initiation of treatment. Instruct patients tostore FT218 nightly dose packets and FT218 doses in a secure place, outof the reach of children and pets.

Alcohol or Sedative Hypnotics

Advise patients and/or caregivers that alcohol and other sedativehypnotics should not be taken with FT218.

Sedation

Inform patients and/or caregivers that the patient is likely to fallasleep quickly after taking FT218 (often within 5 and usually within 15minutes), but the time it takes to fall asleep can vary from night tonight. The sudden onset of sleep, including in a standing position orwhile rising from bed, has led to falls complicated by injuries, in somecases requiring hospitalization. Instruct patients that they shouldremain in bed following ingestion of their dose.

Respiratory Depression and Sleep-Disordered Breathing

Inform patients that FT218 may impair respiratory drive, especially inpatients with compromised respiratory function, and may cause apnea.

Depression and Suicidality

Instruct patients to contact a healthcare provider immediately if theydevelop depressed mood, markedly diminished interest or pleasure inusual activities, significant change in weight and/or appetite,psychomotor agitation or retardation, increased fatigue, feelings ofguilt or worthlessness, slowed thinking or impaired concentration, orsuicidal ideation.

Other Behavioral or Psychiatric Adverse Reactions

Inform patients that FT218 can cause behavioral or psychiatric adversereactions, including confusion, anxiety, and psychosis. Instruct them tonotify their healthcare provider if any of these types of symptomsoccur.

Sleepwalking

Instruct patients that FT218 has been associated with sleepwalking andother behaviors during sleep, and to contact their healthcare providerif this occurs.

Sodium Intake

Instruct patients that FT218 contains a significant amount of sodium andpatients who are sensitive to sodium intake (e.g., those with heartfailure, hypertension, or renal impairment) should limit their sodiumintake.

Medication Guide FT218 (sodium oxybate) extended-release oralsuspension, CIII

Read this Medication Guide carefully before you start taking FT218 andeach time you get a refill. There may be new information. Thisinformation does not take the place of talking to your doctor about yourmedical condition or treatment.

What is the Most Important Information I should Know about FT218?

FT218 is a central nervous system (CNS) depressant. Taking FT218 withother CNS depressants such as medicines used to make you fall asleep,including opioid analgesics, benzodiazepines, sedating antidepressants,antipsychotics, sedating anti-epileptic medicines, general anesthetics,muscle relaxants, alcohol, or street drugs, may cause serious medicalproblems, including:

-   -   trouble breathing (respiratory depression)    -   low blood pressure (hypotension)    -   changes in alertness (drowsiness)    -   dizziness (syncope)    -   death

Ask your doctor if you are not sure if you are taking a medicine listedabove.

FT218 is a federal controlled substance (CIII). The active ingredient ofFT218 is a form of gamma-hydroxybutyrate (GHB) that is also a federalcontrolled substance (CI). Abuse of illegal GHB, either alone or withother CNS depressants may cause serious medical problems, including:

-   -   seizure    -   trouble breathing (respiratory depression)    -   changes in alertness (drossiness)    -   coma    -   death

Call your doctor right away if you have any of these serious sideeffects.

Anyone who takes FT218 should not do anything that requires them to befully awake or is dangerous, including driving a car, using heavymachinery, or flying an airplane, for at least 6 hours after takingFT218. Those activities should not be done until you know how FT218affects you. Keep FT218 in a safe place to prevent abuse and misuse.Selling or giving away FT218 may harm others, and is against the law.Tell your doctor if you have ever abused or been dependent on alcohol,prescription medicines, or street drugs.

Because of the risk of CNS depression, abuse, and misuse, FT218 isavailable only by prescription and filled through certified pharmaciesin the FT218 REMS Program. You must be enrolled in the FT218 REMSProgram to receive FT218. Before you receive FT218, your doctor orpharmacist will make sure that you understand how to use FT218 safelyand effectively. If you have any questions about FT218, ask your doctoror call the FT218 REMS Program.

What is FT218?

FT218 is a prescription medicine used to treat the following symptoms inpeople with narcolepsy:

-   -   sudden onset of weak or paralyzed muscles (cataplexy)    -   excessive daytime sleepiness (EDS)

It is not known if FT218 is safe and effective in people less than 18years of age.

Do not take FT218 if you:

-   -   take other sleep medicines or sedatives (medicines that cause        sleepiness)    -   drink alcohol    -   have a rare problem called succinic semialdehyde dehydrogenase        deficiency

Before taking FT218, tell your doctor about all medical conditions,including if you:

-   -   have a history of drug abuse.    -   have short periods of not breathing while sleeping (sleep apnea)    -   snore, have trouble breathing, or have lung problems. You may        have a higher chance of having serious breathing problems when        taking FT218.    -   have or had depression or have tried to harm yourself or        themselves. You should be watched carefully for new symptoms of        depression.    -   have or had behavior or other psychiatric problems such as:        -   anxiety        -   seeing or hearing things that are not real (hallucinations)        -   feeling more suspicious (paranoia)        -   being out of touch with reality (psychosis)        -   acting aggressive        -   agitation    -   have liver problems    -   are on a salt-restricted diet. FT218 contains a lot of sodium        (salt) and may not be right for you.    -   have high blood pressure    -   have heart failure    -   have kidney problems    -   are pregnant or plan to become pregnant. It is not known if        FT218 can harm your unborn baby.    -   are breastfeeding or plan to breastfeed. FT218 passes into        breast milk. You and your doctor should decide if you will take        FT218 or breastfeed.

Tell your doctor about all the medicines you take, includingprescription and over-the-counter medicines, vitamins, and herbalsupplements. Especially, tell your doctor if you take other medicines tohelp you sleep (sedatives). Know the medicines you take. Keep a list ofthem to show your doctor and pharmacist when you get a new medicine.

How should I Take FT218?

Read the Instructions for Use at the end of this Medication Guide fordetailed instructions on how to take FT218. Take FT218 exactly as yourdoctor tells you to take it. FT218 can cause physical dependence andcraving for the medicine when it is not taken as directed. Never changethe FT218 dose without talking to your doctor.

FT218 can cause sleep very quickly without feeling drowsy. Some peoplefall asleep within 5 minutes and most fall asleep within 15 minutes. Thetime it takes to fall asleep might be different from night to night.Falling asleep quickly, including while standing or while getting upfrom the bed, has led to falls with injuries that have required somepeople to be hospitalized. If you take too much FT218, call your doctoror go to the nearest hospital emergency room right away.

What are the possible side effects of FT218?

FT218 may cause serious side effects, including:

-   -   See “What is the most important information I should know about        FT218?”    -   breathing problems, including:        -   slower breathing        -   trouble breathing        -   short periods of not breathing while sleeping (sleep apnea).            People who already have breathing or lung problems have a            higher chance of having breathing problems when they use            FT218.    -   mental health problems, including:        -   confusion        -   seeing or hearing things that are not real (hallucinations)        -   unusual or disturbing thoughts (abnormal thinking)        -   feeling anxious or upset        -   depression        -   thoughts of killing yourself or trying to kill yourself        -   increased tiredness        -   feelings of guilt or worthlessness        -   difficulty concentrating

Call your doctor right away if you have symptoms of mental healthproblems.

-   -   sleepwalking. Sleepwalking can cause injuries. Call your doctor        if you start sleepwalking. Your doctor should check you.

The most common side effects of FT218 include:

-   -   nausea    -   dizziness    -   bedwetting    -   headache    -   decreased appetite    -   vomiting    -   anxiety

Side effects may increase when taking higher doses of FT218.

These are not all the possible side effects of FT218. For moreinformation, ask your doctor or pharmacist. Call your doctor for medicaladvice about side effects. You may report side effects to FDA at1-800-FDA-1088.

How should I Store FT218?

Store FT218 in the original nightly dose packets prior to mixing withwater. After mixing with water, store FT218 in the mixing cup providedin each kit. Store FT218 at room between 68° F. to 77° F. (20° C. to 25°C.). FT218 suspension may be consumed within 30 minutes of preparation.When you have finished using the FT218 nightly dose packet, dispose ofit in the trash. FT218 comes in a child-resistant package. Keep FT218and all medicines out of the reach of children and pets.

General Information about the Safe and Effective Use of FT218.

Medicines are sometimes prescribed for purposes other than those listedin a Medication Guide. Do not use FT218 for a condition for which it wasnot prescribed. Do not give FT218 to other people, even if they have thesame symptoms. It may harm them. You can ask your pharmacist or doctorfor information about FT218 that is written for health professionals.

What are the Ingredients in FT218?

Active ingredients: sodium oxybate. Additional ingredients:microcrystalline cellulose spheres, povidone K30, hydrogenated vegetableoil, methacrylic acid copolymer, malic acid, xanthan gum, hydroxyethylcellulose, carrageenan, magnesium stearate.

Example 22: Mixing Cup Assessment

The design of the mixing cup (e.g. mixing aid) was assessed for impacton shaking and reconstitution of the composition, any residual material,and resistance to breakage in a drop test.

Shaking Study

The following tests were performed to assess the impact of the new clearmixing aid with “A” (50 mL) and “B” (25 mL) volume markers and white cap(i.e. commercial mixing aid) on the shaking and reconstitution step ofthe sodium oxybate ER oral suspension (FT218). The mixing aid wascompared to reconstitution of the sodium oxybate ER suspension preparedin a 110 mL Dram Amber mixing aid with a white cap (i.e. clinical mixingaid).

The protocol used for preparing the suspension in either mixing aid wasas follows:

-   -   Add half of the total content of the mixing aid with water        (about 50 mL)    -   Pour the content of a 4.5 g or 9 g dose unit in the mixing aid    -   Close the mixing aid and shake vigorously    -   Introduce the content of the mixing aid in the dissolution        vessel    -   Add about ¼ of the volume of the mixing aid with water (about 25        mL)    -   Close the mixing aid and shake vigorously    -   Introduce the content of the mixing aid in the dissolution        vessel

The purpose of this study was to demonstrate that different shakingtimes have no effect on the dissolution of FT218 formulations in eitherthe clinical or commercial mixing aid and very minimal residual drug isleft if the second rinsing step is omitted. This impact was evaluatedby: visual observation (picture of the mixing aid after the rinsingstep); calculating the weight of the residual suspension material afterexecuting the rinsing step; and comparison of the 0.1N HCl dissolutionprofiles generated in each condition.

Reconstitution protocol and introduction of the suspension in thedissolution vessel included the following steps:

-   -   Weigh the mixing aid before use;    -   Add about 50 mL of tap water (volume marker A)    -   Pour the content of a 4.5 or 9 g dose sachet,    -   Close the mixing aid and shake vigorously (duration 1),    -   Pour the content of the mixing aid in the dissolution vessel    -   Add ¼ of the volume of the mixing aid (about 25 mL) with tap        water (volume marker B)    -   Close the mixing aid and shake vigorously (duration 2)    -   Pour the content of the mixing aid in the dissolution vessel    -   Take a picture of remaining material in the mixing aid;    -   Weigh the mixing aid after use and calculate the remaining        quantity of suspension in the mixing aid

Three trials, each with different durations for mixing were performedaccording to Table 26 below.

TABLE 26 Mixing Durations Duration 1 Duration 2 Trial (reconstitutionstep) (rinsing step) Trial 1 60 s 10 s Trial 2 30 s  5 s Trail 3 10 s  5s

Table 27 shows the results of Trial 1, Table 28 shows the results ofTrial 2, and Table 29 shows the results of Trial 3 for a 4.5 g dose ofFT218.

TABLE 27 Mixing Aid and Residual Suspension Weight for Trial 1Commercial Clinical mixing aid mixing aid Empty mixing aid 20.7521 g20.7556 g 20.6472 g 20.9528 g Mixing aid after 20.9353 g  20.873 g21.3992 g 21.9166 g rinsing Residual suspension  0.1832 g  0.1174 g 0.7520 g  0.9638 g material

TABLE 28 Mixing Aid and Residual Suspension Weight for Trial 2Commercial Clinical mixing aid mixing aid Empty mixing aid  20.771 g20.7553 g 20.7478 g  20.825 g Mixing aid after 20.9129 g 20.8727 g21.4482 g 21.4718 g rinsing Residual suspension  0.1419 g  0.1174 g 0.7004 g  0.6468 g material

TABLE 29 Mixing Aid and Residual Suspension Weight for Trial 3Commercial Clinical mixing aid mixing aid Empty mixing aid 20.7798 g20.7622 g 20.6482 g 20.5647 g Mixing aid after 20.9313 g  20.848 g21.2636 g 21.3438 g rinsing Residual suspension  0.1515 g  0.0858 g 0.6154 g  0.7791 g material

FIG. 138A shows dissolution profiles for Trials 1-3 for 4.5 g with thetwo different cups. The dissolution test used paddle apparatus USP II,in 1800 mL of pH 6.8 and/or 0.1 N HCl medium and an RP-HPLC assay withspectrophotometric detection of collected samples. The HPLC assayincludes an external calibration using standard solutions of sodiumoxybate (GHB) and/or gamma-butyrolactone (GBL). For the sodium oxybatefor ER oral suspension in 0.1N HCl medium, 40%<T1 hour <60% dissolved,45%<T3 hours <65% dissolved, and T12 hours >80% dissolved.

In a first step, the result of the analysis was initially expressed ing/L as the assayed sodium oxybate concentration using the GHBcalibration slope and as the assayed gamma-butyrolactone concentrationusing the GBL calibration slope. The assayed gamma-butyrolactoneconcentration was then converted in GHB taking into account themolecular mass of both compounds (“GBL equivalent GHB”). In a secondstep, the sum of both concentrations was adjusted with the volume ofdissolution vessel before the sampling and converted in % of dissolvedsodium oxybate. For this example, the result, expressed in % dissolved,was the mean of 2 determinations.

Table 30 shows the results of Trial 1, Table 31 shows the results ofTrial 2, and Table 32 shows the results of Trial 3 for a 9 g dose ofFT218. FIG. 138B shows dissolution profiles for Trials 1-3 for 9 g withthe two different cups.

TABLE 30 Mixing Aid and Residual Suspension Weight for Trial 1Commercial Clinical mixing aid mixing aid Empty mixing aid 20.6412 g20.7386 g 20.7414 g 20.7925 g Mixing aid after 20.9772 g 20.8566 g21.3499 g 21.3597 g rinsing Residual suspension  0.2360 g  0.1180 g 0.6085 g  0.5672 g material

TABLE 31 Mixing Aid and Residual Suspension Weight for Trial 2Commercial Clinical mixing aid mixing aid Empty mixing aid 20.7441 g20.7386 g 20.9105 g 20.8712 g Mixing aid after 20.8882 g 20.9354 g21.5980 g 21.7062 g rinsing Residual suspension  0.1441 g  0.1968 g 0.6875 g  0.8350 g material

TABLE 32 Mixing Aid and Residual Suspension Weight for Trial 3Commercial Clinical mixing aid mixing aid Empty mixing aid 20.7797 g 20.752 g 20.6974 g 20.7965 g Mixing aid after 20.8823 g 20.9073 g21.3399 g 21.6625 g rinsing Residual suspension  0.1026 g  0.1553 g 0.6425 g  0.8660 g material

Visual inspection showed a difference between the two types of mixingaids. The quantity of residual material was visually higher in the amberclinical mixing aid than in colorless commercial mixing aid. The mass ofresidual material after the rinsing step confirmed this observation withmasses of no more than 0.2 g with the colorless commercial mixing aidand the residual masses ranging from 0.6 to 1.0 g for the clinicalmixing aid. The amount of remaining suspension did not depend on theamount of sample introduced into the mixing aid (about 7.1 g for thedrug product dosed at 4.5 g and 14.2 g for the drug product dosed at 9.0g), nor on the stirring time tested, but on the type of mixing aid: thepresence of additive in commercial mixing aid reduces the amount ofproduct left in the mixing aid.

In terms of dissolution, all individual and mean dissolution data complywith the specifications. Mean dissolution profiles could be consideredas similar and superimposable whatever the shaking time and the type ofmixing aid (or amount of residual sample not introduced in the vessel)but individual profiles seems to be more heterogeneous for the trial 3i.e. for the shortest shaking time (duration 1) and particularly for thedrug product dosed at 9.0 g.

The reconstitution protocol and assay of the suspension and residualmaterial in the commercial mixing aid by HPLC included the followingsteps:

-   -   Add about 50 mL of tap water in the mixing aid (volume marker A)    -   Pour the content of a 4.5 or 9 g dose unit    -   Close the mixing aid and shake vigorously (duration 1)    -   Pour the content of the mixing aid in a 500 mL volumetric flask        and perform the assay of the delivered dose.    -   Rinse the mixing aid with diluent several times to ensure that        all the drug is removed and place into a separate 100 mL        volumetric flask.    -   Determine the residual drug according to the HPLC assay.

The assay consisted of a solid-liquid extraction in mobile phase andmethanol and of an RP-HPLC assay with spectrophotometric detection at210 nm. The Agilent HPLC system D034, fitted with a refrigeratedauto-sampler and auto-injector, a DAD UV detector containing a cell witha 10 mm optical path-length, and a column temperature regulation system,was used. Duration 1 for Trial 1 was 60 s and duration 1 for Trial 2 was10 s. Table 33 shows the results of Trial 1 and Table 34 shows theresults of Trial 2. FIG. 139A shows a chromatogram for Trial 1 and FIG.139B shows a chromatogram for Trial 2.

TABLE 33 Sodium oxybate content in % respect to the label claim after 60s of reconstitution Trial 1 Label Claim dose 4.5 g Label Claim dose 9 g% delivered dose after 60 s shaking % respect to 100.13255 100.81816label claim 99.31198 101.02804 Mean value (%) 99.7 100.9 % residualmaterial in the mixing aid % respect to 1.15476 1.72903 label claim1.08915 1.43801 Mean value (%) 1.1 1.6

TABLE 34 Sodium oxybate content in % respect to the label claim after 10s of reconstitution Trial 2 Label Claim dose 4.5 g Label Claim dose 9 g% delivered dose after 10 s shaking % respect to 97.89911 99.45515 labelclaim 99.44576 100.60717 Mean value (%) 98.7 100 % residual material inthe mixing aid % respect to 1.45817 0.95056 label claim 0.72853 1.03431Mean value (%) 1.1 1.0

In terms of delivered dose, individual and mean data range from 97.9 to100.8% and comply with specifications of from 90.0 to 110.0 of the labelclaim. The residual drug left in the mixing aid if the second rinsingstep is omitted, ranges from 1.0 to 1.6% of the label claim. This amountof residual material does not depend on the amount of sample introducedinto the mixing aid (about 7.1 g for the drug product dosed at 4.5 g and14.2 g for the drug product dosed at 9.0 g), nor on the stirring timetested.

Quality Testing

30 mixing aids were filled to the “A” line with water. An adapter in atorque wrench and clamp was used to torque the cap on the cup 10in/lbs+2 in/lbs. The mixing aids were then dropped from 18 inches onto ahard floor surface. No cracks, breaks, or leaks were observed in any ofthe mixing aids.

30 mixing aids were filled to the “A” line with water. An adapter in atorque wrench and clamp was used to torque the cap on the cup 10in/lbs+2 in/lbs. The mixing aids were then shaken by hand for 1 minute.No leaks were observed.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains. It willbe apparent to those skilled in the art that various modifications andvariations may be made in the present invention without departing fromthe scope or spirit of the invention. Other embodiments of the inventionwill be apparent to those skilled in the art from consideration of thespecification and practice of the invention disclosed herein. It isintended that the specification and examples be considered as exemplaryonly, with a true scope and spirit of the invention being indicated bythe following claims.

Example 23: Labeling for Additional FT218 Embodiment Warning: CentralNervous System (CNS) Depression and Abuse and Misuse

Central Nervous System Depression

FT218 (sodium oxybate) is a CNS depressant. In clinical trials atrecommended doses, obtundation and clinically significant respiratorydepression occurred in adult patients treated with twice-nightly sodiumoxybate. Many patients who received sodium oxybate during clinicaltrials in narcolepsy were receiving central nervous system stimulants.

Abuse and Misuse

FT218 (sodium oxybate) is the sodium salt of gamma-hydroxybutyrate(GHB). Abuse or misuse of illicit GHB, either alone or in combinationwith other CNS depressants, is associated with CNS adverse reactions,including seizure, respiratory depression, decreases in the level ofconsciousness, coma, and death [see Warnings and Precautions (5.2)].

Because of the risks of CNS depression and abuse and misuse, FT218 isavailable only through a restricted program under a Risk Evaluation andMitigation Strategy (REMS) called the FT218 REMS. INDICATIONS AND USAGE

FT218 is indicated for the treatment of cataplexy or excessive daytimesleepiness (EDS) in adults with narcolepsy.

Dosage and Administration

Dosing Information

The recommended starting dosage is 4.5 grams (g) once per nightadministered orally. Increase the dosage by 1.5 g per night at weeklyintervals to the effective dosage range of 6 g to 9 g once per nightorally. The dosage may be gradually titrated based on efficacy andtolerability. Doses higher than 9 g per night have not been studied andshould not ordinarily be administered.

Important Administration Instructions

FT218 is taken orally as a single dose at bedtime. Prepare the dose ofFT218 prior to bedtime. Prior to ingestion, each dose of FT218 should besuspended in approximately ⅓ cup (approximately 80 mL) of water in thedosing cup provided. Do not use hot water. After mixing, consume FT218within 30 minutes.

Take FT218 at least 2 hours after eating.

Patients should take FT218 while in bed and lie down immediately afterdosing as FT218 may cause them to fall asleep abruptly without firstfeeling drowsy. Patients will often fall asleep within 5 minutes oftaking FT218, and will usually fall asleep within 15 minutes, though thetime it takes any individual patient to fall asleep may vary from nightto night. Rarely, patients may take up to 2 hours to fall asleep.Patients should remain in bed following ingestion of FT218.

Dosage Forms and Strengths

For extended-release oral suspension: FT218 is a white to off-whitepowder provided in packets of 4.5 g, 6 g, 7.5 g, or 9 g of sodiumoxybate.

Contraindications

FT218 is contraindicated for use in:

-   -   combination with sedative hypnotics    -   combination with alcohol    -   patients with succinic semialdehyde dehydrogenase deficiency

Postmarketing Experience

The following adverse reactions have been identified during postapprovaluse of sodium oxybate. Because these reactions are reported voluntarilyfrom a population of uncertain size, it is not always possible toreliably estimate their frequency or establish a causal relationship todrug exposure:

Arthralgia, decreased appetite, fall*, fluid retention, hangover,headache, hypersensitivity, hypertension, memory impairment, nocturia,panic attack, vision blurred, and weight decreased. *The sudden onset ofsleep in patients taking sodium oxybate, including in a standingposition or while rising from bed, has led to falls complicated byinjuries, in some cases requiring hospitalization.

Drug Interactions

Alcohol, Sedative Hypnotics, and CNS Depressants

FT218 is contraindicated for use in combination with alcohol or sedativehypnotics. Use of other CNS depressants may potentiate theCNS-depressant effects of FT218 [see Warnings and Precautions (5.1)].Consumption of alcohol while taking FT218 may result in a more rapidrelease of the dose of sodium oxybate.

Divalproex Sodium

FT218, like other oxybate products, may have a pharmacodynamicinteraction that could increase the risk of certain adverse reactions.Appropriate dosage adjustments of LYMRYZ cannot be made with the dosagestrengths available; however, if concomitant use of FT218 and divalproexsodium is warranted, prescribers are advised to monitor patient responseclosely and adjust dosage accordingly.

Use in Specific Populations

Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with theuse of sodium oxybate in pregnant women. Oral administration of sodiumoxybate to pregnant rats (150, 350, or 1,000 mg/kg/day) or rabbits (300,600, or 1,200 mg/kg/day) throughout organogenesis produced no clearevidence of developmental toxicity; however, oral administration to ratsthroughout pregnancy and lactation resulted in increased stillbirths anddecreased offspring postnatal viability and growth, at a clinicallyrelevant dose [see Data].

In the U.S. general population, the estimated background risk of majorbirth defects and miscarriage in clinically recognized pregnancies is24% and 15-20%, respectively. The background risk of major birth defectsand miscarriage for the indicated population is unknown.

Clinical Considerations

Labor or Delivery

FT218 has not been studied in labor or delivery. In obstetric anesthesiausing an injectable formulation of sodium oxybate, newborns had stablecardiovascular and respiratory measures but were very sleepy, causing aslight decrease in Apgar scores. There was a fall in the rate of uterinecontractions 20 minutes after injection. Placental transfer is rapid andgamma-hydroxybutyrate (GHB) has been detected in newborns at deliveryafter intravenous administration of GHB to mothers. Subsequent effectsof sodium oxybate on later growth, development, and maturation in humansare unknown.

Data

Animal Data

Oral administration of sodium oxybate to pregnant rats (150, 350, or1,000 mg/kg/day) or rabbits (300, 600, or 1,200 mg/kg/day) throughoutorganogenesis produced no clear evidence of developmental toxicity. Thehighest doses tested in rats and rabbits were approximately 1 and 3times, respectively, the maximum recommended human dose (MRHD) of 9 gper night on a body surface area (mg/m2) basis.

Oral administration of sodium oxybate (150, 350, or 1,000 mg/kg/day) torats throughout pregnancy and lactation resulted in increasedstillbirths and decreased offspring postnatal viability and body weightgain at the highest dose tested. The no-effect dose for pre- andpost-natal developmental toxicity in rats is less than the MRHD on amg/m2 basis.

Lactation

Risk Summary

GHB is excreted in human milk after oral administration of sodiumoxybate. There is insufficient information on the risk to a breastfedinfant, and there is insufficient information on milk production innursing mothers. The developmental and health benefits of breastfeedingshould be considered along with the mother's clinical need for FT218 andany potential adverse effects on the breastfed infant from FT218 or fromthe underlying maternal condition.

Geriatric Use

Clinical studies of FT218 or twice-nightly sodium oxybate in patientswith narcolepsy did not include sufficient numbers of subjects age 65years and older to determine whether they respond differently fromyounger subjects. In controlled trials of twice-nightly sodium oxybatein another population, 39 (5%) of 874 patients were 65 years or older.Discontinuations of treatment due to adverse reactions were increased inthe elderly compared to younger adults (21% vs. 19%). Frequency ofheadaches was markedly increased in the elderly (39% vs. 19%). The mostcommon adverse reactions were similar in both age categories. Ingeneral, dose selection for an elderly patient should be cautious,usually starting at the low end of the dosing range, reflecting thegreater frequency of decreased hepatic, renal, or cardiac function, andof concomitant disease or other drug therapy.

Hepatic Impairment

Because of an increase in exposure to FT218, FT218 should not beinitiated in patients with hepatic impairment because appropriate dosageadjustments for initiation of LYMRYZ cannot be made with the availabledosage strengths [see Clinical Pharmacology (12.3)]. Patients withhepatic impairment who have been titrated to a maintenance dosage ofanother oxybate product can be switched to FT218 if the appropriatedosage strength is available.

Drug Abuse and Dependence

Controlled Substance

FT218 is a Schedule III controlled substance under the FederalControlled Substances Act. Non-medical use of FT218 could lead topenalties assessed under the higher Schedule I controls.

Abuse

FT218 (sodium oxybate), the sodium salt of GHB, produces dose-dependentcentral nervous system effects, including hypnotic and positivesubjective reinforcing effects. The onset of effect is rapid, enhancingits potential for abuse or misuse.

Drug abuse is the intentional non-therapeutic use of a drug product orsubstance, even once, for its desirable psychological or physiologicaleffects. Misuse is the intentional use, for therapeutic purposes of adrug by an individual in a way other than prescribed by a health careprovider or for whom it was not prescribed. Drug misuse and abuse mayoccur with or without progression to addiction. Drug addiction is acluster of behavioral, cognitive, and physiological phenomena that mayinclude a strong desire to take the drug, difficulties in controllingdrug use (e.g., continuing drug use despite harmful consequences, givinga higher priority to drug use than other activities and obligations),and possible tolerance or physical dependence.

The rapid onset of sedation, coupled with the amnestic features of GHB,particularly when combined with alcohol, has proven to be dangerous forthe voluntary and involuntary user (e.g., assault victim).

Illicit GHB is abused in social settings primarily by young adults. Someof the doses estimated to be abused are in a similar dosage range tothat used for treatment of patients with cataplexy. GHB has somecommonalities with ethanol over a limited dose range, and some crosstolerance with ethanol has been reported as well. Cases of severedependence and craving for GHB have been reported when the drug is takenaround the clock. Patterns of abuse indicative of dependence include: 1)the use of increasingly large doses, 2) increased frequency of use, and3) continued use despite adverse consequences.

Because illicit use and abuse of GHB have been reported, physiciansshould carefully evaluate patients for a history of drug abuse andfollow such patients closely, observing them for signs of misuse orabuse of GHB (e.g., increase in size or frequency of dosing,drug-seeking behavior, feigned cataplexy). Dispose of FT218 according tostate and federal regulations. It is safe to dispose of FT218 down thesanitary sewer.

Dependence

Physical dependence is a state that develops as a result ofphysiological adaptation in response to repeated drug use, manifested bywithdrawal signs and symptoms after abrupt discontinuation or asignificant dose reduction of a drug. There have been case reports ofwithdrawal, ranging from mild to severe, following discontinuation ofillicit use of GHB at frequent repeated doses (18 g to 250 g per day) inexcess of the recommended dosage range. Signs and symptoms of GHBwithdrawal following abrupt discontinuation included insomnia,restlessness, anxiety, psychosis, lethargy, nausea, tremor, sweating,muscle cramps, tachycardia, headache, dizziness, rebound fatigue andsleepiness, confusion, and, particularly in the case of severewithdrawal, visual hallucinations, agitation, and delirium. Thesesymptoms generally abated in 3 to 14 days. In cases of severewithdrawal, hospitalization may be required. The discontinuation effectsof FT218 have not been systematically evaluated in controlled clinicaltrials. In the clinical trial experience with twice-nightly sodiumoxybate in narcolepsy/cataplexy patients at recommended doses, twopatients reported anxiety and one reported insomnia following abruptdiscontinuation at the termination of the clinical trial; in the twopatients with anxiety, the frequency of cataplexy had increased markedlyat the same time.

Tolerance

Tolerance is a physiological state characterized by a reduced responseto a drug after repeated administration (i.e., a higher dose of a drugis required to product the same effect that was once obtained at a lowerdose). Tolerance to FT218 has not been systematically studied incontrolled clinical trials. There have been some case reports ofsymptoms of tolerance developing after illicit use at dosages far inexcess of the recommended FT218 dosage regimen. Clinical studies oftwice-nightly sodium oxybate in the treatment of alcohol withdrawalsuggest a potential cross-tolerance with alcohol. The safety andeffectiveness of FT218 in the treatment of alcohol withdrawal have notbeen established.

Overdosage

Human Experience

Information regarding overdose with FT218 is derived largely fromreports in the medical literature that describe symptoms and signs inindividuals who have ingested GHB illicitly. In these circumstances, theco-ingestion of other drugs and alcohol was common and may haveinfluenced the presentation and severity of clinical manifestations ofoverdose.

In adult clinical trials of twice-nightly sodium oxybate, two cases ofoverdose with sodium oxybate were reported. In the first case, anestimated dose of 150 g, more than 15 times the maximum recommendeddose, caused a patient to be unresponsive with brief periods of apneaand to be incontinent of urine and feces. This individual recoveredwithout sequelae. In the second case, death was reported following amultiple drug overdose consisting of sodium oxybate and numerous otherdrugs.

Signs and Symptoms

Information about signs and symptoms associated with overdosage withFT218 derives from reports of illicit use of GHB. Patient presentationfollowing overdose is influenced by the dose ingested, the time sinceingestion, the co-ingestion of other drugs and alcohol, and the fed orfasted state. Patients have exhibited varying degrees of depressedconsciousness that may fluctuate rapidly between a confusional, agitatedcombative state with ataxia and coma. Emesis (even when obtunded),diaphoresis, headache, and impaired psychomotor skills have beenobserved. No typical pupillary changes have been described to assist indiagnosis; pupillary reactivity to light is maintained. Blurred visionhas been reported. An increasing depth of coma has been observed athigher doses. Myoclonus and tonic-clonic seizures have been reported.

Respiration may be unaffected or compromised in rate and depth.Cheyne-Stokes respiration and apnea have been observed. Bradycardia andhypothermia may accompany unconsciousness, as well as muscularhypotonia, but tendon reflexes remain intact.

Recommended Treatment of Overdose

General symptomatic and supportive care should be institutedimmediately, and gastric decontamination may be considered ifco-ingestants are suspected. Because emesis may occur in the presence ofobtundation, appropriate posture (left lateral recumbent position) andprotection of the airway by intubation may be warranted. Although thegag reflex may be absent in deeply comatose patients, even unconsciouspatients may become combative to intubation, and rapid-sequenceinduction (without the use of sedative) should be considered. Vitalsigns and consciousness should be closely monitored. The bradycardiareported with GHB overdose has been responsive to atropine intravenousadministration. No reversal of the central depressant effects of FT218can be expected from naloxone or flumazenil administration. The use ofhemodialysis and other forms of extracorporeal drug removal have notbeen studied in GHB overdose. However, due to the rapid metabolism ofsodium oxybate, these measures are not warranted.

Poison Control Center

As with the management of all cases of drug overdosage, the possibilityof multiple drug ingestion should be considered. The healthcare provideris encouraged to collect urine and blood samples for routine toxicologicscreening, and to consult with a regional poison control center(1-800-222-1222) for current treatment recommendations.

Description

Sodium oxybate, a CNS depressant, is the active ingredient in FT218 forextended-release oral suspension. The chemical name for sodium oxybateis sodium 4-hydroxybutyrate. The molecular formula is C₄H₇NaO₃, and themolecular weight is 126.09 g/mole. The chemical structure is:

Sodium oxybate is a white to off-white solid powder.

Each single dose packet of FT218 contains 4.5 g, 6 g, 7.5 g, or 9 g ofsodium oxybate, equivalent to 3.7 g, 5.0 g, 6.2 g, or 7.4 g of oxybate,respectively. The inactive ingredients are carrageenan, hydrogenatedvegetable oil, hydroxyethyl cellulose, magnesium stearate, malic acid,methacrylic acid copolymer, microcrystalline cellulose, povidone, andxanthan gum.

Clinical Pharmacology

Mechanism of Action

FT218 is a CNS depressant. The mechanism of action of FT218 in thetreatment of narcolepsy is unknown. Sodium oxybate is the sodium salt ofgamma-hydroxybutyrate (GHB), an endogenous compound and metabolite ofthe neurotransmitter GABA. It is hypothesized that the therapeuticeffects of FT218 on cataplexy and excessive daytime sleepiness aremediated through GABAB actions at noradrenergic and dopaminergicneurons, as well as at thalamocortical neurons.

Pharmacokinetics

Absorption

Following oral administration of twice-nightly sodium oxybate, GHB isabsorbed rapidly across the clinical dose range, with an absolutebioavailability of about 88%. Following oral administration of FT218,the peak plasma concentrations (C_(max)) following administration of one6 g dose was 66 mcg/mL, and the time to peak plasma concentration(T_(max)) was 1.5 hours. Following oral administration of FT218, theplasma levels of GHB increased more than dose-proportionally, with Cmaxincreasing approximately 2-fold, and AUC increasing 2.3-fold, as totaldaily dose is doubled from 4.5 g to 9 g.

Effect of Food

Administration of FT218 immediately after a high-fat meal resulted in amean reduction in C_(max) and AUC of GHB by 33% and 16%, respectively,and average T_(max) increased from 0.5 hr to 1.5 hr.

Effect of Ethanol

An in vitro study showed alcohol-induced dose-dumping of sodium oxybatefrom extended-release oral suspension at 1 hour, and increase of drugrelease to approximately 60% at 2 hours in the presence of 20% alcohol.Effects of 5% and 10% alcohol on drug release were not significant up to14 hours. No in vivo data on the effect of alcohol on drug exposure areavailable.

Effect of Water Temperature

An in vitro dissolution study showed that FT218 mixed with hot water(90° C.) resulted in a dose-dumping phenomenon for the release of sodiumoxybate, whereas warm water (50° C.) did not significantly affect thedrug release from the extended-release suspension.

Distribution

GHB is a hydrophilic compound with an apparent volume of distributionaveraging 190 mL/kg to 384 mL/kg. At GHB concentrations ranging from 3mcg/mL to 300 mcg/mL, less than 1% is bound to plasma proteins.

Elimination

Metabolism

Animal studies indicate that metabolism is the major elimination pathwayfor GHB, producing carbon dioxide and water via the tricarboxylic acid(Krebs) cycle, and secondarily by beta-oxidation. The primary pathwayinvolves a cytosolic NADP+-linked enzyme, GHB dehydrogenase, whichcatalyzes the conversion of GHB to succinic semialdehyde, which is thenbiotransformed to succinic acid by the enzyme succinic semialdehydedehydrogenase. Succinic acid enters the Krebs cycle where it ismetabolized to carbon dioxide and water. A second mitochondrialoxidoreductase enzyme, a transhydrogenase, also catalyzes the conversionto succinic semialdehyde in the presence of α-ketoglutarate. Analternate pathway of biotransformation involves β-oxidation via3,4-dihydroxybutyrate to carbon dioxide and water. No active metaboliteshave been identified.

Excretion

The clearance of GHB is almost entirely by biotransformation to carbondioxide, which is then eliminated by expiration. On average, less than5% of unchanged drug appears in human urine within 6 to 8 hours afterdosing. Fecal excretion is negligible. GHB has an elimination half-lifeof 0.5 to 1 hour.

Specific Population

Geriatric Patients

There is limited experience with FT218 in the elderly. Results from apharmacokinetic study of twice-nightly sodium oxybate (n=20) in anotherstudied population indicate that the pharmacokinetic characteristics ofGHB are consistent among younger (age 48 to 64 years) and older (age 65to 75 years) adults.

Pediatric Patients

The pharmacokinetics of FT218 in patients younger than 18 years of agehave not been studied.

Male and Female Patients

In a study of 18 female and 18 male healthy adult volunteers, no genderdifferences were detected in the pharmacokinetics of GHB following atwice-nightly oral dose of sodium oxybate 4.5 g.

Racial or Ethnic Groups

There are insufficient data to evaluate any pharmacokinetic differencesamong races.

Patients with Renal Impairment

No pharmacokinetic study in patients with renal impairment has beenconducted.

Patients with Hepatic Impairment

The pharmacokinetics of GHB in 16 cirrhotic patients, half withoutascites (Child's Class A) and half with ascites (Child's Class C), werecompared to the kinetics in 8 subjects with normal hepatic function,after a single sodium oxybate oral dose of 25 mg/kg. AUC values weredouble in the cirrhotic patients, with apparent oral clearance reducedfrom 9.1 mL/min/kg in healthy adults to 4.5 and 4.1 mL/min/kg in Class Aand Class C patients, respectively. Elimination half-life wassignificantly longer in Class C and Class A patients than in controlpatients (mean t_(1/2) of 59 and 32 minutes, respectively, versus 22minutes in control patients). FT218 should not be initiated in patientswith liver impairment.

Drug Interaction Studies

Studies in vitro with pooled human liver microsomes indicate that sodiumoxybate does not significantly inhibit the activities of the humanisoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A, up to theconcentration of 3 mM (378 mcg/mL), a level considerably higher thanlevels achieved with recommended doses.

Drug interaction studies in healthy adults (age 18 to 50 years) wereconducted with FT218 and divalproex sodium:

Divalproex sodium: Co-administration of a single dose of FT218 (6 g)with divalproex sodium ER at steady state resulted in comparablesystemic exposure to GHB, as shown by plasma C_(max) and AUC values. Asingle dose of FT218 (6 g) did not appear to affect the pharmacokineticsof divalproex sodium. However, a potential pharmacodynamic interactionbetween FT218 and divalproex sodium cannot be ruled out.

Drug interaction studies in healthy adults (age 18 to 50 years) wereconducted with twice-nightly sodium oxybate and diclofenac andibuprofen:

-   -   Diclofenac: Co-administration of sodium oxybate (6 g per day as        two equal doses of 3 grams dosed four hours apart) with        diclofenac (50 mg/dose twice per day) showed no significant        differences in systemic exposure to GHB. Co-administration did        not appear to affect the pharmacokinetics of diclofenac.    -   Ibuprofen: Co-administration of sodium oxybate (6 g per day as        two equal doses of 3 grams dosed four hours apart) with        ibuprofen (800 mg/dose four times per day also dosed four hours        apart) resulted in comparable systemic exposure to GHB as shown        by plasma C_(max) and AUC values. Co-administration did not        affect the pharmacokinetics of ibuprofen.

Drug interaction studies in healthy adults demonstrated nopharmacokinetic interactions between twice-nightly sodium oxybate andprotriptyline hydrochloride, zolpidem tartrate, and modafinil. Also,there were no pharmacokinetic interactions with the alcoholdehydrogenase inhibitor fomepizole. However, pharmacodynamicinteractions with these drugs cannot be ruled out. Alteration of gastricpH with omeprazole produced no significant change in thepharmacokinetics of GHB. In addition, drug interaction studies inhealthy adults demonstrated no pharmacokinetic or clinically significantpharmacodynamic interactions between twice-nightly sodium oxybate andduloxetine HCl.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Administration of sodium oxybate to rats at oral doses of up to 1,000mg/kg/day for 83 (males) or 104 (females) weeks resulted in no increasein tumors. Plasma exposure (AUC) at the highest dose tested was 2 timesthat in humans at the maximum recommended human dose (MRHD) of 9 g pernight.

The results of 2-year carcinogenicity studies in mouse and rat withgamma-butyrolactone, a compound that is metabolized to sodium oxybate invivo, showed no clear evidence of carcinogenic activity. The plasma AUCsof sodium oxybate achieved at the highest doses tested in these studieswere less than that in humans at the MRHD.

Mutagenesis

Sodium oxybate was negative in the in vitro bacterial gene mutationassay, an in vitro chromosomal aberration assay in mammalian cells, andin an in vivo rat micronucleus assay.

Impairment of Fertility

Oral administration of sodium oxybate (150, 350, or 1,000 mg/kg/day) tomale and female rats prior to and throughout mating and continuing infemales through early gestation resulted in no adverse effects onfertility. The highest dose tested is approximately equal to the MRHD ona mg/m2 basis.

How Supplied/Storage and Handling

How Supplied

FT218 is a blend of white to off-white granules for extended-releaseoral suspension in water. Each carton contains either 7 or 30 packets ofFT218, a dosing cup, Prescribing Information, Instructions for Use, andMedication Guide.

Dose packets contain a single dose of FT218 provided in 4.5 g, 6 g, 7.5g, and 9 g doses.

Strength Package Size NDC Number 4.5 g  7 packets NDC XXXXX-XXX-XX 30packets NDC XXXXX-XXX-XX   6 g  7 packets NDC XXXXX-XXX-XX 30 packetsNDC XXXXX-XXX-XX 7.5 g  7 packets NDC XXXXX-XXX-XX 30 packets NDCXXXXX-XXX-XX   9 g  7 packets NDC XXXXX-XXX-XX 30 packets NDCXXXXX-XXX-XX

Storage

Keep out of reach of children.

FT218 should be stored at 20° C. to 25° C. (68° F. to 77° F.);excursions permitted to 15° C. to 30° C. (59° F. to 86° F.) (see USPControlled Room Temperature).

Suspensions should be consumed within 30 minutes.

Handling and Disposal

FT218 is a Schedule III drug under the Controlled Substances Act. FT218should be handled according to state and federal regulations. It is safeto dispose of FT218 down the sanitary sewer.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (MedicationGuide and Instructions for Use).

Central Nervous System Depression

Inform patients that FT218 can cause central nervous system depression,including respiratory depression, hypotension, profound sedation,syncope, and death. Instruct patients to not engage in activitiesrequiring mental alertness or motor coordination, including operatinghazardous machinery, for at least 6 hours after taking FT218. Instructpatients to inform their healthcare providers of all the medicationsthey take.

Abuse and Misuse

Inform patients that the active ingredient of FT218 isgamma-hydroxybutyrate (GHB), which is associated with serious adversereactions with illicit use and abuse.

FT218 REMS

FT218 is available only through a restricted program called the FT218REMS. Inform the patient of the following notable requirements:

-   -   FT218 is dispensed only by pharmacies that are specially        certified    -   FT218 will be dispensed and shipped only to patients who are        enrolled in the FT218 REMS

FT218 is available only from certified pharmacies participating in theprogram. Therefore, provide patients with the telephone number andwebsite for information on how to obtain the product.

Alcohol or Sedative Hypnotics

Advise patients that alcohol and other sedative hypnotics should not betaken with FT218 [see Warnings and Precautions (5.1)].

Sedation

Inform patients that they are likely to fall asleep quickly after takingFT218 (often within 5 and usually within 15 minutes), but the time ittakes to fall asleep can vary from night to night. The sudden onset ofsleep, including in a standing position or while rising from bed, hasled to falls complicated by injuries, in some cases requiringhospitalization. Instruct patients that they should remain in bedfollowing ingestion of their dose.

Food Effects on FT218

Inform patients that FT218 should be taken at least 2 hours aftereating.

Respiratory Depression and Sleep-Disordered Breathing

Inform patients that FT218 may impair respiratory drive, especially inpatients with compromised respiratory function, and may cause apnea.

Depression and Suicidality

Instruct patients to contact a healthcare provider immediately if theydevelop depressed mood, markedly diminished interest or pleasure inusual activities, significant change in weight and/or appetite,psychomotor agitation or retardation, increased fatigue, feelings ofguilt or worthlessness, slowed thinking or impaired concentration, orsuicidal ideation.

Other Behavioral or Psychiatric Adverse Reactions

Inform patients that FT218 can cause behavioral or psychiatric adversereactions, including confusion, anxiety, and psychosis. Instruct them tonotify their healthcare provider if any of these types of symptomsoccur.

Sleepwalking

Instruct patients that FT218 has been associated with sleepwalking andother behaviors during sleep, and to contact their healthcare providerif this occurs.

Sodium Intake

Instruct patients that FT218 contains a significant amount of sodium andpatients who are sensitive to sodium intake (e.g., those with heartfailure, hypertension, or renal impairment) should limit their sodiumintake.

What is claimed is:
 1. A pharmaceutical composition comprising:immediate release particles, each of which comprises: a core consistingof microcrystalline cellulose; and a sodium oxybate loaded layercovering the core and containing a binder comprising povidone, whereinthe immediate release particles have a volume mean diameter of 150 to400 microns; delayed release particles having a pH trigger, each delayedrelease particle comprising: a core consisting of microcrystallinecellulose; a sodium oxybate loaded layer covering the core of eachdelayed release particle and containing a binder comprising povidone;and a coating covering the sodium oxybate loaded layer of each delayedrelease particle, wherein the coating consists essentially ofhydrogenated vegetable oil, methacrylic acid copolymer type C andmethacrylic acid copolymer type B, wherein a weight ratio of thehydrogenated vegetable oil to the copolymers types B and C is from 0.4to 4, and wherein the coating is from 10 to 50% of the weight of thedelayed release particles, and wherein the delayed release particleshave a volume mean diameter of 200 to 800 microns; a suspending orviscosifying agent comprising 2% to 5% by weight of the composition, thesuspending or viscosifying agent being a mixture of xanthan gum,carrageenan and hydroxyethylcellulose; and an acidifying agentcomprising 1.2% to 5% by weight of the composition, the acidifying agentbeing malic acid, wherein the composition comprises from 3.0 to 12.0 gof sodium oxybate, wherein a ratio of sodium oxybate in the immediaterelease particles and the delayed release particles is from 40/60 to60/40, and wherein the composition is in the form of a powder that isintended to be suspended in water prior to oral administration.